EP1412361B1 - Substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid derivatives serving as nmda antagonists - Google Patents

Substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid derivatives serving as nmda antagonists Download PDF

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EP1412361B1
EP1412361B1 EP02764838A EP02764838A EP1412361B1 EP 1412361 B1 EP1412361 B1 EP 1412361B1 EP 02764838 A EP02764838 A EP 02764838A EP 02764838 A EP02764838 A EP 02764838A EP 1412361 B1 EP1412361 B1 EP 1412361B1
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oxa
tetrahydro
fluorene
carboxylic acid
azabenzo
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German (de)
French (fr)
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EP1412361A1 (en
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Matthias Gerlach
Michael Przewosny
Werner Günter ENGLBERGER
Elke Reissmüller
Petra Bloms-Funke
Corinna Maul
Utz-Peter Jagusch
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Gruenenthal GmbH
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Gruenenthal GmbH
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Definitions

  • the present invention relates to substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives, and processes for their preparation, medicaments containing these compounds and their use for the preparation of medicaments for certain indications, especially for the treatment of pain.
  • Opioids exert their analgesic effect by binding to membrane-bound receptors belonging to the family of so-called G protein-coupled receptors.
  • the biochemical and pharmacological characterization of subtypes of these receptors now has the hope aroused that subtype-specific opioids have a different effect / side effect profile than eg morphine. Further pharmacological investigations have in the meantime made the existence of several subtypes of these opioid receptors ( ⁇ 1 , ⁇ 2 , ⁇ 1 , ⁇ 2 , ⁇ 3 , ⁇ 1 and ⁇ 2 ) probable.
  • there are other receptors and ion channels that are significantly involved in the system of pain development and pain transmission.
  • NMDA ion channel an essential part of the communication of synapses takes place over it. This channel controls calcium ion exchange between the neuronal cell and its environment. Knowledge of the physiological importance of ion channel-selective substances has been gained through the development of the patch-clamp technique. Thus, the effect of NMDA antagonists on the influence of calcium ions in the cell interior can be clearly demonstrated. It also turned out that these substances have their own antinociceptive potential (eg ketamine). It is important that the mechanism of action is quite different, as for example in the opiate, because by NMDA antagonists is directly intervened in the crucial calcium balance of the cells in the pain transmission.
  • the 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention have a marked analgesic effect and are also NMDA antagonists which attack selectively at the glycine binding site.
  • salt means any form of the active ingredient according to the invention in which it assumes an ionic form or is charged and is coupled with a counterion (a cation or anion) or is in solution.
  • a counterion a cation or anion
  • salts of the active ingredient with other molecules and ions in particular complexes that are complexed via ionic interactions.
  • physiologically compatible salt with cations or bases refers to salts of at least one of the compounds according to the invention-usually a (deprotonated) acid-as an anion having at least one, preferably inorganic, cation which is physiologically-in particular when used in humans and / or mammalian.
  • Particularly preferred are the salts of the alkali and alkaline earth metals but also with NH 4 + , but especially (mono-) or (di) sodium, (mono-) or (di) potassium, magnesium or calcium salts.
  • physiologically tolerable salt with anions or acids is understood as meaning salts of at least one of the compounds according to the invention-usually, for example, nitrogen-protonated-as a cation having at least one anion, which is physiologically particularly useful in humans and / or mammals. are compatible.
  • a physiologically acceptable acid namely salts of the respective active ingredient with inorganic or organic acids, which are physiologically compatible - in particular when used in humans and / or mammals.
  • physiologically acceptable salts of certain acids are salts of: hydrochloric, hydrobromic, sulfuric, methanesulfonic, formic, acetic, oxalic, succinic, tartaric, mandelic, fumaric, lactic, citric, glutamic, 1,1-dioxo-1,2-dihydrol1b6 benzo [d] isothiazol-3-one (saccharic acid), monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, Nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid.
  • Particularly preferred is the hydrochloride salt.
  • the invention also provides processes for the preparation of salts according to the invention of a substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative.
  • the so-called basic process described here is a trifluoroacetic acid-mediated, preferably “one-pot” process in which one aromatic amine, one aldehyde and one electron-rich olefin component react with each other.
  • substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to formula I are prepared.
  • a decisive advantage of the process according to the invention is that the process according to a domino reaction (imine formation and downstream aza-Diels-Alder reaction) leads very selectively to the desired systems, in addition to good yields.
  • the method of the invention differs in addition to its ease of operation also by its purification method.
  • non-polar solvents such as n-hexane
  • the products can be obtained in high purity. Otherwise, their purification succeeds by means of column chromatography.
  • compounds of the formula I can be obtained diastereomerically pure by the washing processes with nonpolar solvents, such as, for example, n- hexane, or by crystallization of their salts.
  • a compound of formula I upon completion of the formation of a compound of formula I, the compound is contacted with a base or acid which may already contain the desired cation or anion, and the resulting salt is subsequently purified.
  • a base or acid which may already contain the desired cation or anion
  • the resulting salt is subsequently purified.
  • Most of the reagents used here, in particular according to formula II, III and IV are commercially available or can be prepared by simple, known in the art synthesis steps.
  • OH-SH and NH 2 groups may possibly undergo undesirable side reactions. It is therefore preferred to provide these with protective groups or in the case of Replace NH 2 with NO 2 and, before purification of the final product, remove the protective group or reduce the NO 2 group.
  • Another object of the application is therefore a modification of the method described above, wherein in the starting compounds at least one OH group by an OSi (Ph) 2 tert-butyl group, at least one SH group by a Sp-methoxybenzyl group and / or at least one NH 2 group has been replaced by a NO 2 group and before purification of the final product at least one - preferably all - OSi (Ph) 2 tert-butyl group / n, with tetrabutylammonium fluoride in tetrahydrofuran and / or at least one - preferably all - p-methoxybenzyl / n with a metal amine, preferably sodium, cleaved and / or at least one - preferably all - NO 2 group / n is reduced to NH 2 .
  • carboxylic acid or thiocarboxylic acid groups under the reaction conditions mentioned may not be stable, so that it is preferred to use their methyl ester in the reactions and the process product then with KOH solution or NaOH solution in methanol at 40 ° C - 60 ° C to saponify.
  • Another object of the invention is therefore a modification of the method described above, in which before the purification of the final product, a process product having at least one C (O) OCH 3 - OC (O) OCH 3 - and / or C (S) OCH 3 - Group with KOH solution or NaOH solution in methanol or ethanol at 0 ° C - 100 ° C, preferably 40 ° C - 60 ° C, saponified.
  • 1 normal aqueous alkali for example NaOH or KOH
  • the salts in particular the imino acids, or carboxylic acids, preferably the sodium or potassium salts, are obtained as mostly colorless solids.
  • the potassium or sodium salts with potassium or.
  • To produce sodium trimethylsilanolate Ed Laganis, BL Chenard; Tetrahedron Letters 25, 5831-5834 (1984 )).
  • Potassium or Natriumtrimethylsilanolat is thereby dissolved under nitrogen in an organic solvent (eg dichloromethane, toluene, THF) and the ester, or the acid added in one portion.
  • the reaction mixture is stirred for several hours at room temperature and filtered off.
  • the usually colorless solid is washed and dried in vacuo.
  • the potassium or sodium salts are obtained as solids.
  • the substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to the invention are toxicologically harmless, so that they are suitable as pharmaceutical active ingredient in medicaments.
  • Another object of the invention is therefore also a medicament containing as active ingredient at least one inventive substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to formula I in the form shown or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular of the hydrates; especially in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; and optionally containing suitable additives and / or adjuvants and / or optionally further active ingredients.
  • the medicaments according to the invention can be administered as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, patches or aerosols and in addition to at least one substituted 5,6,6a according to the invention, 11b-Tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative, depending on the galenic form, optionally carrier materials, fillers, solvents, diluents, dyes and / or binders.
  • excipients and the amounts to be used depend on whether the drug is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or topical, for example on skin infections, mucous membranes and on the eyes, to be applied.
  • preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable, for parenteral, topical and inhalative administration solutions, suspensions, readily reconstitutable dry preparations and sprays.
  • the amount of active substance to be administered to the patient varies depending on the patient Weight of the patient, the mode of administration, the indication and the severity of the disease.
  • the substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to the invention are preferably used for the treatment of pain, in particular chronic and neuropathic pain, but also in migraine, so that a Another subject of the invention is the use of at least one substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to the invention of formula I in the form shown or in the form of the acid or base or in In the form of its salts, in particular of the physiologically tolerated salts, or in the form of its solvates, in particular hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoiso
  • NMDA antagonists are known to have inter alia a neuroprotective effect and therefore can also be used well in neurodegeneration and damage-associated diseases, such as Parkinson's disease and Huntington's disease, etc.
  • Further indications of the NMDA antagonists according to the invention are epilepsy, glaucoma, osteoporosis, ototoxicity, the withdrawal symptoms associated with alcohol and / or drug abuse, the stroke, and related cerebral ischaemias, cerebral infarctions, cerebral edema, hypoxia, anoxia, as well as anxiolysis and anesthesia.
  • Another object of the invention is therefore the use of at least one substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the formula I according to the invention; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment / prophylaxis of epilepsy, Parkinson's disease, Huntington's disease, glaucoma, ototoxicity, withdrawal symptoms in alcohol and
  • substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivative of the invention are also very suitable for other indications, in particular for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea.
  • a further subject of the application is therefore the use of at least one substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the formula I according to the invention; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea
  • a further subject of the application is therefore the use of at least one substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the formula I according to the invention; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the preparation of a medicament for the treatment / prophylaxis of schizophrenia, Alzheimer's disease, psychoses due to increased levels of amino acids,
  • Another object of the invention is a method of treating a non-human mammal or human that requires treatment of medically relevant symptoms by administering a therapeutically significant dose of a substituted 5,6,6a, 11b-tetrahydro-7-oxa-5 of the invention aza-benzo [c] fluorene-6-carboxylic acid derivative according to formula I; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; or a drug of the invention.
  • the invention particularly relates to corresponding methods for the treatment of pain, in particular of neuropathic and / or chronic pain and / or for the treatment of migraine for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea, for the treatment / prophylaxis of / in epilepsy, for morbus Parkinson's disease, Huntington's disease, glaucoma, osteoporosis, ototoxicity, withdrawal symptoms in alcohol and / or drug abuse, stroke, cerebral ischaemias, cerebral infarctions, cerebral edema, hypoxia, anoxia and / or anxiolysis and / or anesthesia or for the treatment / prophylaxis of / at Schizophrenia, Alzheimer's disease, psychosis due to elevated levels of amino acids, AIDS dementia, encephalomyelitis, Tourette's syndrome, perinatal asphyxia inflammatory and allergic reactions, depression, drug and / or alcohol abuse, gastritis, diabetes, cardiovascular disease, respiratory
  • the analysis was carried out by ESI mass spectrometry.
  • connections are numbered, whereby the indication in brackets always corresponds to the number of the assigned connection.
  • both the glyoxylic acid and the glyoxal ester preferably the alkyl ester, in particular the ethyl or Methyl ester, to understand.
  • the reaction mixture was stirred at 20 ° C in one of the stirring blocks for 10 h. Thereafter, the reaction solution was filtered off. The tube was rinsed twice with 1.5 ml each of a 7.5% NaHCO 3 solution.
  • the reaction mixture was added to a vortexer with 2 ml of ethyl acetate and shaken. To form the phase boundary was briefly centrifuged in the centrifuge. The phase boundary was optically detected and the organic phase was pipetted off.
  • the aqueous phase was added again with 2 ml of ethyl acetate, shaken, centrifuged and the organic phase was pipetted off.
  • the combined organic phases were dried over 2.4 g MgSO 4 (granulated).
  • the solvent was removed in a vacuum centrifuge. Characterization of the free 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid or ester is carried out by ESI mass spectrometry.
  • saponification can be carried out by methods known to the person skilled in the art both using an automated and normal basic method, for example with KOH solution or NaOH solution in methanol or ethanol at 0 ° C.-100 ° C., preferably 40 ° ° C - 60 ° C.
  • Compound 1 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and the unsubstituted benzofuran, wherein the resulting ester was finally saponified.
  • Compound 2 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 5-methoxybenzofuran, wherein the resulting ester was finally saponified.
  • Compound 3 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-methylbenzofuran, wherein the resulting ester was finally saponified.
  • Compound 4 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-ethylbenzofuran wherein the resulting ester was finally saponified.
  • Compound 5 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-methoxybenzofuran, wherein the resulting ester was finally saponified.
  • Compound 6 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-fluorobenzofuran, wherein the resulting ester was finally saponified.
  • Compound 7 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-chlorobenzofuran, wherein the resulting ester was finally saponified.
  • Compound 8 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-bromobenzofuran, wherein the resulting ester was finally saponified.
  • Compound 9 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-iodobenzofuran, wherein the resulting ester was finally saponified.
  • Compound 10 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and benzofuran-7-carboxylic acid, wherein the resulting ester was finally saponified.
  • Compound 11 was prepared according to the basic method of Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and the 5-methylbenzofuran, wherein the resulting ester was finally saponified.
  • Compound 12 was prepared according to the basic method of Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 5-fluorobenzofuran, wherein the resulting ester was finally saponified.
  • Compound 13 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 5-chlorobenzofuran, wherein the resulting ester was finally saponified.
  • Compound 14 was prepared by the basic method of Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and the 5-bromobenzofuran, wherein the resulting ester was finally saponified.
  • Compound 15 was prepared by the basic method of Example 0 from 3,5-dichloroaniline, the ethyl glyoxalate and the 5-iodobenzofuran, wherein the resulting ester was finally saponified.
  • Compound 16 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and benzofuran-5-carboxylic acid, wherein the resulting ester was finally saponified.
  • Compound 17 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 5-cyanobenzofuran, wherein the resulting ester was finally saponified.
  • Example 18 General presentation of the salts with cations using the example of the compounds according to one of Examples 1-17.
  • the salts, in particular the imino acids, preferably the sodium or potassium salts are obtained as mostly colorless solids.
  • the potassium or sodium salts with potassium or.
  • sodium trimethylsilanolate Ed Laganis, BL Chenard; Tetrahedron Letters 25, 5831-5834 (1984 )
  • Potassium or Natriumtrimethylsilanolat is dissolved under nitrogen in an organic solvent (dichloromethane, toluene, THF) and the ester, or acid, added in one portion.
  • the reaction mixture is stirred for four hours at room temperature and filtered off.
  • the usually colorless solid is washed with diethyl ether and dried in vacuo.
  • the potassium or sodium salts are obtained as solids.
  • the compounds according to Examples 19 to 35 are sodium salts of compounds 1 to 17 prepared by these exemplary procedures, the compounds according to Examples 36 to 52 the correspondingly prepared potassium salts.
  • Compound 19 was prepared by the method of Example 18 from Compound 1 .
  • Compound 20 was prepared by the method of Example 18 from Compound 2 .
  • Compound 21 was prepared by the method of Example 18 from Compound 3 .
  • Compound 22 was prepared by the method of Example 18 from compound 4 .
  • Compound 23 was prepared by the method of Example 18 from compound 5 .
  • Compound 24 was prepared by the method of Example 18 from Compound 6 .
  • Compound 25 was prepared by the method of Example 18 from Compound 7 .
  • Compound 26 was prepared by the method of Example 18 from compound 8 .
  • Compound 27 was prepared by the method of Example 18 from compound 9 .
  • Compound 28 was prepared by the method of Example 18 from Compound 10 .
  • Compound 29 was prepared by the method of Example 18 from compound 11 .
  • Compound 30 was prepared by the method of Example 18 from compound 12 .
  • Compound 31 was prepared by the method of Example 18 from Compound 13 .
  • Compound 32 was prepared by the method of Example 18 from Compound 14 .
  • Compound 33 was prepared by the method of Example 18 from Compound 15 .
  • Compound 34 was prepared by the method of Example 18 from Compound 16 .
  • Compound 35 was prepared by the method of Example 18 from Compound 17 .
  • Compound 36 was prepared by the method of Example 18 from Compound 1 .
  • Compound 37 was prepared by the method of Example 18 from Compound 2 .
  • Compound 38 was prepared by the method of Example 18 from Compound 3 .
  • Compound 39 was prepared by the method of Example 18 from Compound 4 .
  • Compound 40 was prepared by the method of Example 18 from Compound 5 .
  • Compound 41 was prepared by the method of Example 18 from Compound 6 .
  • Compound 42 was prepared by the method of Example 18 from Compound 7 .
  • Compound 43 was prepared by the method of Example 18 from compound 8 .
  • Compound 44 was prepared by the method of Example 18 from compound 9 .
  • Compound 45 was prepared by the method of Example 18 from Compound 10 .
  • Compound 46 was prepared by the method of Example 18 from Compound 11 .
  • Compound 47 was prepared by the method of Example 18 from Compound 12 .
  • Compound 31 was prepared by the method of Example 18 from Compound 13 .
  • Compound 49 was prepared by the method of Example 18 from compound 14 .
  • Compound 50 was prepared by the method of Example 18 from Compound 15 .
  • Compound 51 was prepared by the method of Example 18 from Compound 16 .
  • Compound 52 was prepared by the method of Example 18 from Compound 17 .
  • Example 53 General presentation of the salts with anions using the example of the hydrochloride salt of the compounds according to one of Examples 1-17.
  • the compounds according to Examples 54 to 70 are hydrochloride salts of compounds 1 to 17 prepared by this exemplary procedure.
  • Compound 54 was prepared by the method of Example 53 from Compound 1 .
  • Compound 55 was prepared by the method of Example 53 from Compound 2 .
  • Compound 56 was prepared by the method of Example 53 from Compound 3 .
  • Compound 57 was prepared by the method of Example 53 from Compound 4 .
  • Compound 58 was prepared by the method of Example 53 from Compound 5 .
  • Compound 59 was prepared by the method of Example 53 from Compound 6 .
  • Compound 60 was prepared by the method of Example 53 from Compound 7 .
  • Compound 61 was prepared by the method of Example 53 from compound 8 .
  • Compound 62 was prepared by the method of Example 53 from Compound 9 .
  • Compound 63 was prepared by the method of Example 53 from Compound 10 .
  • Compound 64 was prepared by the method of Example 53 from Compound 11 .
  • Compound 65 was prepared by the method of Example 53 from Compound 12 .
  • Compound 66 was prepared by the method of Example 53 from Compound 13 .
  • Compound 67 was prepared by the method of Example 53 from Compound 14 .
  • Compound 68 was prepared by the method of Example 53 from Compound 15 .
  • Compound 69 was prepared by the method of Example 53 from Compound 16 .
  • Compound 70 was prepared by the method of Example 53 from Compound 17 .
  • Receptor binding (glycine binding site of the NMDA receptor channel)
  • the cortex and hippocampus were prepared from freshly taken rat chickens and dissolved in 5 mmol / l TRIS acetate buffer, 0.32 mol / l sucrose pH 7.4 (10 ml / g fresh weight) with a Potter homogenizer (Braun / Melsungen 10 Piston strokes at 500 rpm) with ice cooling homogenized and then centrifuged for 10 minutes at 1000 g and 4 ° C.
  • the first supernatant was collected and the sediment was resuspended with 5 mmol / l TRIS acetate buffer, 0.32 mol / l sucrose pH 7.4 (5 ml / g original fresh weight) with the Potter homogenizer (10 strokes at 500 rpm) Ice cooling homogenized and centrifuged for 10 minutes at 1000 g and 4 ° C. The resulting supernatant was combined with the supernatant from the first centrifugation and centrifuged at 17,000 g for 20 minutes at 4 ° C.
  • the membrane sediment was thawed and taken up with ice cold 5 mmol / l TRIS acetate buffer, 0.1% saponin (w / v) pH 7.0 (10 ml / g original fresh weight) and homogenized with 10 strokes at 500 rpm then centrifuged for 20 minutes at 50,000 g and 4 ° C. The resulting supernatant was discarded and the sediment was taken up in a small volume with 5 mMo / l TRIS acetate buffer pH 7.0 (about 2 ml / g original fresh weight) and homogenized again with 10 strokes of the flask at 500 rpm.
  • the membrane homogenate was adjusted to a protein concentration of 10 mg protein / ml with 5 mmol / l TRIS acetate buffer pH 7.0 and frozen in aliquots until testing.
  • aliquots were thinned 1:10 with 5 mM Tris acetate buffer pH 7.0, homogenized with 10 strokes at 500 rpm using the Potter homogenizer (10 strokes at 500 rpm) with ice cooling and for 60 minutes at 55,000 g centrifuged at 4 ° C.
  • the supernatant was decanted and the membrane sediment with ice-cold 50 mmol / l TRIS acetate buffer pH 7.0 to a protein concentration of 1 mg / ml adjusted and again homogenized with 10 strokes of the piston at 500 rpm and kept in suspension with stirring on a magnetic stirrer in an ice bath. From this membrane homogenate in each case 100 .mu.l were used per 1 ml batch in the receptor binding test (0.1 mg protein / ml in the final batch).
  • the buffer used was 50 mmol / l TRIS acetate buffer pH 7.0 and the radioactive ligand 1 nmol / l ( 3 H) MDL 105,519 (Baron BM et al., 1996).
  • the proportion of non-specific binding was determined in the presence of 1 mmol / l glycine.
  • the compounds according to the invention were added in concentration series and the displacement of the radioactive ligand from its specific binding to the glycine binding site of the NMDA receptor channel was determined.
  • the respective triplicate batches were incubated for 120 minutes at 4 ° C. and then harvested by filtration through glass fiber filter mats (GF / B) to determine the radioactive ligand bound to the membrane homogenate.
  • the radioactivity retained on the glass fiber filters was measured after addition of scintillator in the ⁇ -counter.
  • the affinity of the compounds according to the invention for the glycine binding site of the NMDA receptor channel was calculated as IC 50 (concentration with 50% displacement of the radioactive ligand from its specific binding) according to the law of mass action by means of nonlinear regression and is shown in Table 1 after conversion (according to the Cheng Prussoff relationship) as the Ki value (mean of 3 independent experiments) or as a percentage of the previously bound radioactive ligand so that is displaced from its specific binding at a concentration of 10 .mu.mol / l of the substance to be tested inventive substance.
  • the investigations for the determination of the antinociceptive activity of the compounds of the formula I according to the invention were carried out in a formalin test on male rats (Sprague-Dawley, 150-170 g).
  • the first (early) phase (0-15 min after formalin injection) and the second (late) phase (15-60 min after formalin injection) are distinguished ( D. Dubuisson, SG Dennis, Pain 4, 161-174 (1977 )).
  • the early phase represents a model of acute pain as a direct response to formalin injection, while the late phase is considered a model of persistent (chronic) pain ( TJ Coderre, J. Katz, AL Vaccarino, R. Melzack, Pain, Vol. 52, p. 259, 1993 ).
  • the compounds according to the invention were investigated in the second phase of the formalin test in order to obtain statements about substance effects in chronic / inflammatory pain.
  • a single subcutaneous injection of formalin (50 ⁇ l, 5%) into the dorsal side of the right hindpaw induced a nociceptive reaction in freely moving test animals, which is reflected in the following behavioral parameters: lifting and holding the affected paw (score 1), shaking or twitching (score 2), licking and biting (score 3).
  • the differing behaviors due to formalin injection were continuously monitored by observation of the animals in the late phase of the formalin test and weighted differently in a score. Normal behavior, in which the animal evenly loaded all four paws, was registered as score 0.
  • the application time before the formalin injection was selected (intraperitoneal: 15 min, intravenous: 5 min).
  • the described behavior (score 1 - 3) of the animals are reduced, possibly even reversed.
  • the comparison was done with control animals that had received vehicle (solvent) before formalin application.
  • the nociceptive behavior was calculated as the so-called pain rate (PR).
  • PR pain rate
  • the different behavioral parameters received a different weighting (factor 0, 1, 2, 3).
  • Example 73 Parenteral administration form.
  • 38.5 g of compound 1 are dissolved in 1 liter of water for injection at room temperature and then adjusted to isotonic conditions by adding anhydrous glucose for injection.

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Abstract

Substituted 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid compounds, and processes for the production thereof, pharmaceutical compositions containing these compounds and the use thereof in treatment methods and for the production of pharmaceutical preparations for specific indications, in particular for the treatment of pain.

Description

Die vorliegende Erfindung betrifft substituierte 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivate, sowie Verfahren zu deren Herstellung, Arzneimittel enthaltend diese Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln für bestimmte Indikationen, insbesondere zur Behandlung von Schmerz.The present invention relates to substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives, and processes for their preparation, medicaments containing these compounds and their use for the preparation of medicaments for certain indications, especially for the treatment of pain.

Die Behandlung chronischer und nicht chronischer Schmerzzustände hat in der Medizin eine große Bedeutung. Es besteht ein weltweiter Bedarf an gut wirksamen Schmerztherapien für eine patientengerechte und zielorientierte Behandlung chronischer und nicht chronischer Schmerzzustände, wobei hierunter die erfolgreiche und zufriedenstellende Schmerzbehandlung für den Patienten zu verstehen ist. Dies zeigt sich in der großen Anzahl von wissenschaftlichen Arbeiten, die auf dem Gebiet der angewandten Analgetik bzw. der Grundlagenforschung zur Nociception in letzter Zeit erschienen sind.
Klassische Opioide wie Morphin sind bei der Therapie starker bis stärkster Schmerzen gut wirksam. Ihr Einsatz wird jedoch durch die bekannten Nebenwirkungen z.B. Atemdepression, Erbrechen, Sedierung, Obstipation und Toleranzentwicklung limitiert. Außerdem sind sie bei neuropathischen oder inzidentiellen Schmerzen, unter denen insbesondere Tumorpatienten leiden, weniger wirksam.
Opioide entfalten ihre analgetische Wirkung durch Bindung an membranständige Rezeptoren, die zur Familie der sogenannten G-Proteingekoppelten Rezeptoren gehören. Die biochemische und pharmakologische Charakterisierung von Subtypen dieser Rezeptoren hat nun die Hoffnung geweckt, daß subtypenspezifische Opioide über ein anderes Wirkungs-/Nebenwirkungsprofil als z.B. Morphin verfügen. Weitere pharmakologische Untersuchungen haben inzwischen die Existenz mehrerer Subtypen dieser Opioidrezeptoren (µ1, µ2, κ1, κ2, κ3, δ1 und δ2) wahrscheinlich gemacht. Daneben gibt es weitere Rezeptoren und Ionenkanäle, die wesentlich an dem System der Schmerzentstehung und Schmerzweiterleitung beteiligt sind. Besonders wichtig ist dabei der NMDA-lonenkanal: Über ihn läuft ein wesentlicher Teil der Kommunikation von Synapsen ab. Durch diesen Kanal wird der Calcium-lonenaustausch zwischen neuronaler Zelle und seiner Umgebung gesteuert.
Kenntnisse über die physiologische Bedeutung von Ionenkanal-selektiven Substanzen sind durch die Entwicklung der patch-clamp-Technik gewonnen worden. So läßt sich eindeutig die Wirkung von NMDA-Antagonisten auf den Einfluß von Calcium-lonen in das Zellinnere nachweisen. Es stellte sich auch dabei heraus, daß diese Substanzen über ein eigenständiges antinociceptives Potential verfügen (z.B. Ketamin). Wichtig dabei ist, daß der Wirkmechanismus ein ganz anderer ist, wie beispielsweise bei den Opiaten, denn durch NMDA-Antagonisten wird direkt in den entscheidenden Calciumhaushalt der Zellen bei der Schmerzweiterleitung eingegriffen. Daher besteht erstmalig die Möglichkeit, die Behandlung von neuropathischen Schmerzformen erfolgreich durchzuführen.
Verschiedene NMDA-Antagonisten, wobei es sich in diesem Falle um Tetrahydrochinolinderivate handelte, wurden bereits in den Artikeln J. Med. Chem. (1992) 35, 1954-1968 , J. Med. Chem. (1992) 35, 1942-1953 und Med. Chem. Res. (1991) 1; 64-73 sowie den Patentanmeldungen EP 386 839 , WO 97/12879 A1 , WO 98/07704 A1 und WO 98/42673 A1 beschrieben. Dabei wurde insbesondere in den Patentanmeldungen eine Vielzahl von möglichen Indikationen angegeben, unter anderen auch die Schmerztherapie. Die Wirksamkeit und Verwendbarkeit dieser Substanzen ist allerdings weiter offen, so daß hier ein Bedarf nach weiteren Substanzen besteht.The treatment of chronic and non-chronic pain is of great importance in medicine. There is a worldwide need for effective pain therapies for a patient-appropriate and goal-oriented treatment of chronic and non-chronic pain conditions, which is to be understood as the successful and satisfactory pain treatment for the patient. This can be seen in the large number of scientific papers recently published in the field of applied analgesics or basic research on nociception.
Classic opioids such as morphine are effective in the treatment of severe to severe pain. However, their use is limited by the known side effects such as respiratory depression, vomiting, sedation, constipation and tolerance development. In addition, they are less effective in the case of neuropathic or incidental pain, in particular tumor patients.
Opioids exert their analgesic effect by binding to membrane-bound receptors belonging to the family of so-called G protein-coupled receptors. The biochemical and pharmacological characterization of subtypes of these receptors now has the hope aroused that subtype-specific opioids have a different effect / side effect profile than eg morphine. Further pharmacological investigations have in the meantime made the existence of several subtypes of these opioid receptors (μ 1 , μ 2 , κ 1 , κ 2 , κ 3 , δ 1 and δ 2 ) probable. In addition, there are other receptors and ion channels that are significantly involved in the system of pain development and pain transmission. Of particular importance is the NMDA ion channel: an essential part of the communication of synapses takes place over it. This channel controls calcium ion exchange between the neuronal cell and its environment.
Knowledge of the physiological importance of ion channel-selective substances has been gained through the development of the patch-clamp technique. Thus, the effect of NMDA antagonists on the influence of calcium ions in the cell interior can be clearly demonstrated. It also turned out that these substances have their own antinociceptive potential (eg ketamine). It is important that the mechanism of action is quite different, as for example in the opiate, because by NMDA antagonists is directly intervened in the crucial calcium balance of the cells in the pain transmission. Therefore, for the first time, it is possible to successfully carry out the treatment of neuropathic pain.
Various NMDA antagonists, which in this case were tetrahydroquinoline derivatives, have already been described in the articles J. Med. Chem. (1992) 35, 1954-1968 . J. Med. Chem. (1992) 35, 1942-1953 and Med. Chem. Res. (1991) 1; 64-73 as well as the patent applications EP 386 839 . WO 97/12879 A1 . WO 98/07704 A1 and WO 98/42673 A1 described. In particular, in the patent applications a variety of possible indications were given, including the pain therapy. However, the effectiveness and usefulness of these substances is still open, so that there is a need for other substances.

Eine der Erfindung zugrundeliegende Aufgabe bestand darin, analgetisch wirksame Substanzen, insbesondere NMDA-Antagonisten, zur Verfügung zu stellen, die sich zur Schmerztherapie - insbesondere auch chronischer und neuropathischer Schmerzen - eignen. Darüber hinaus sollten diese Substanzen möglichst wenig Nebenwirkungen wie z.B. Übelkeit, Erbrechen, Abhängigkeit, Atemdepression oder Obstipation aufweisen. Entsprechend sind Gegenstand der Erfindung 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivate der allgemeinen Formel I

Figure imgb0001
in dargestellter Form oder in Form ihrer Säuren oder ihrer Basen oder in Form ihrer Salze, insbesondere der physiologisch verträglichen Salze, oder in Form ihrer Solvate, insbesondere der Hydrate; insbesondere in Form ihrer physiologisch verträglichen Salze mit Kationen oder Basen oder mit Anionen oder Säuren; gegebenenfalls in Form ihrer Racemate, ihrer reinen Stereoisomeren, insbesondere Enantiomeren oder Diastereomeren, oder in Form von Mischungen der Stereoisomeren, insbesondere der Enantiomeren oder Diastereomeren, in einem beliebigen Mischungsverhältnis;
worin

  • R1 , R2 , R3 und R4 unabhängig voneinander ausgewählt sind aus H, F, Cl, Br, I, CN, NH2, CH3, C2H5, n-Propyl, i-Propyl, i-Butyl, sek-Butyl, n-Butyl, t-Butyl, CF3, CHF2, SH, OH, OCH3, OC2H5, C(O)OH C(O)OCH3 oder C(O)OC2H5
und
R5=
H,
R6=
H,
R7=
H,
R8=
Cl,
R9=
H und
R10=
Cl ist.
An object underlying the invention was to provide analgesically active substances, in particular NMDA antagonists, which are suitable for the treatment of pain - in particular also chronic and neuropathic pain. In addition, these substances should have as few as possible side effects such as nausea, vomiting, dependence, respiratory depression or constipation. Accordingly, the invention provides 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives of general formula I.
Figure imgb0001
 in the form shown or in the form of their acids or their bases or in the form of their salts, in particular of the physiologically tolerated salts, or in the form of their solvates, in particular the hydrates; in particular in the form of their physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio;
wherein
  • R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, I, CN, NH 2 , CH 3 , C 2 H 5 , n-propyl, i-propyl, i-butyl, sec-butyl, n-butyl, t-butyl, CF 3 , CHF 2 , SH, OH, OCH 3 , OC 2 H 5 , C (O) OH C (O) OCH 3 or C (O) OC 2 H 5
and
R 5 =
H,
R 6 =
H,
R 7 =
H,
R 8 =
Cl,
R 9 =
Dog
R 10 =
Cl is.

Die erfindungsgemäßen 1,2,3,4-Tetrahydrochinolin-2-carbonsäurederivate zeigen eine deutliche analgetische Wirkung und sind auch NMDA-Antagonisten, die selektiv an der Glycin-Bindungsstelle angreifen.The 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives according to the invention have a marked analgesic effect and are also NMDA antagonists which attack selectively at the glycine binding site.

Unter dem Begriff Salz ist jegliche Form des erfindungsgemäßen Wirkstoffes zu verstehen, in dem dieser eine ionische Form annimmt bzw. geladen ist und mit einem Gegenion (einem Kation oder Anion) gekoppelt ist bzw. sich in Lösung befindet. Darunter sind auch Komplexe des Wirkstoffes mit anderen Molekülen und Ionen zu verstehen, insbesondere Komplexe, die über ionische Wechselwirkungen komplexiert sind.The term salt means any form of the active ingredient according to the invention in which it assumes an ionic form or is charged and is coupled with a counterion (a cation or anion) or is in solution. These also include complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions.

Unter dem Begriff des physiologisch verträglichen Salzes mit Kationen oder Basen versteht man im Sinne dieser Erfindung Salze mindestens einer der erfindungsgemäßen Verbindungen - meist einer (deprotonierten) Säure - als Anion mit mindestens einem, vorzugsweise anorganischen, Kation, die physiologisch - insbesondere bei Anwendung im Menschen und/oder Säugetier - verträglich sind. Besonders bevorzugt sind die Salze der Alkali-und Erdalkalimetalle aber auch mit NH4 +, insbesondere aber (Mono-) oder (Di-) Natrium-, (Mono-) oder (Di-) Kalium-, Magnesium- oder Calzium-Salze.In the context of this invention, the term "physiologically compatible salt with cations or bases" refers to salts of at least one of the compounds according to the invention-usually a (deprotonated) acid-as an anion having at least one, preferably inorganic, cation which is physiologically-in particular when used in humans and / or mammalian. Particularly preferred are the salts of the alkali and alkaline earth metals but also with NH 4 + , but especially (mono-) or (di) sodium, (mono-) or (di) potassium, magnesium or calcium salts.

Unter dem Begriff des physiologisch verträglichen Salzes mit Anionen oder Säuren versteht man im Sinne dieser Erfindung Salze mindestens einer der erfindungsgemäßen Verbindungen - meist, beispielsweise am Stickstoff, protoniert - als Kation mit mindestens einem Anion, die physiologischinsbesondere bei Anwendung im Menschen und/oder Säugetier - verträglich sind. Insbesondere versteht man darunter im Sinne dieser Erfindung das mit einer physiologisch verträglichen Säure gebildete Salz, nämlich Salze des jeweiligen Wirkstoffes mit anorganischen bzw. organischen Säuren, die physiologisch - insbesondere bei Anwendung im Menschen und/oder Säugetier - verträglich sind. Beispiele für physiologisch verträgliche Salze bestimmter Säuren sind Salze der: Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Methansulfonsäure, Ameisensäure, Essigsäure, Oxalsäure, Bernsteinsäure, Weinsäure, Mandelsäure, Fumarsäure, Milchsäure, Zitronensäure, Glutaminsäure, 1,1-Dioxo-1,2-dihydrol1b6-benzo[d]isothiazol-3-on (Saccharinsäure), Monomethylsebacinsäure, 5-Oxo-prolin, Hexan-1-sulfonsäure, Nicotinsäure, 2-, 3- oder 4-Aminobenzoesäure, 2,4,6-Trimethylbenzoesäure, a-Liponsäure, Acetylglycin, Acetylsalicylsäure, Hippursäure und/oder Asparaginsäure. Besonders bevorzugt ist das Hydrochlorid-Salz.In the context of this invention, the term "physiologically tolerable salt with anions or acids" is understood as meaning salts of at least one of the compounds according to the invention-usually, for example, nitrogen-protonated-as a cation having at least one anion, which is physiologically particularly useful in humans and / or mammals. are compatible. In particular, for the purposes of this invention, it is understood to mean the salt formed with a physiologically acceptable acid, namely salts of the respective active ingredient with inorganic or organic acids, which are physiologically compatible - in particular when used in humans and / or mammals. Examples of physiologically acceptable salts of certain acids are salts of: hydrochloric, hydrobromic, sulfuric, methanesulfonic, formic, acetic, oxalic, succinic, tartaric, mandelic, fumaric, lactic, citric, glutamic, 1,1-dioxo-1,2-dihydrol1b6 benzo [d] isothiazol-3-one (saccharic acid), monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, Nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and / or aspartic acid. Particularly preferred is the hydrochloride salt.

Bevorzugte Gegenstände sind insbesondere folgende substituierte 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivate bzw. ihre Salze:

  • 1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 1,3-Dichlor-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 1,3-Dichlor-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 1,3-Dichlor-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 1,3-Dichior-8-fluor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 1,3,8-Trichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 8-Brom-1,3-dichlor 5,6,6a,11b-tetrahydro-7-oxa-5-aza- , benzo[c]fluoren-6-carbonsäure,
  • 8-Iod-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6,8-dicarbonsäure,
  • 1,3-Dichlor-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 1,3-Dichlor-10-fluor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 1,3,10-Trichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 10-Brom-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 10-Iod-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
  • 1,3-Dichlor-5,6,6a,1b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6,10-dicarbonsäure oder
  • 1,3-Dichlor-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure,
Preferred articles are in particular the following substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives or their salts:
  • 1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 1,3-dichloro-10-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 1,3-dichloro-8-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 1,3-dichloro-8-ethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 1,3-Dichloro-8-fluoro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 1,3,8-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 8-bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza, benzo [c] fluorene-6-carboxylic acid,
  • 8-iodo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6,8-dicarboxylic acid,
  • 1,3-dichloro-10-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 1,3-dichloro-10-fluoro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 1,3,10-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 10-bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 10-iodo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,
  • 1,3-dichloro-5,6,6a, 1b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6,10-dicarboxylic acid or
  • 1,3-dichloro-10-cyano-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid,

Besonders bevorzugt sind die freien Carbonsäuren oder die Salze der erfindungsgemäßen substituierten 1,2,3,4-Tetrahydrochinolin-2-carbonsäurederivate gemäß Formel I in Form ihrer Alkali-Salze, vorzugsweise der Kalium- oder Natrium-Salze, oder in Form der Salze anorganischer Säuren, vorzugsweise des Hydrochlorids.Particular preference is given to the free carboxylic acids or the salts of the substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivatives of the formula I according to the invention in the form of their alkali salts, preferably of the potassium or sodium salts, or of inorganic salts Acids, preferably the hydrochloride.

Ein weiterer Gegenstand der Erfindung sind auch Verfahren zur Herstellung erfindungsgemäßer Salze eines substituierten 5,6,6a,-11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivats.The invention also provides processes for the preparation of salts according to the invention of a substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative.

In der Literatur sind verschiedene Verfahren zur Darstellung von Tetrahydrochinolinen, dem Grundkörper der erfindungsgemäßen Verbindungen, beschrieben:

  • ein Festphasen-Ansatz ( WO 98/34111 ),
  • mehrstufige Prozessführungen ( WO 98/42673 ; Bioorganic and Medicinal Chemistry Lettetters Vol. 2, S. 371, 1992 ; Journal of Heterocyclic Chemistry Vol. 25, S. 1831, 1988 ; Journal of the Chemical Society, Perkin Transactions I (1989), Seite 2245 ) oder
  • ein Lewis-Säure-katalysiertes "Eintopf"-Verfahren ( Journal of the Chemical Society, Chemical Communications, 1999, S. 651 ; Journal of the American Chemical Society, Vol. 118, S. 8977, 1996 ).
Alle diese Verfahren weisen aber klar einige Nachteile auf.Various processes for the preparation of tetrahydroquinolines, the main body of the compounds according to the invention, are described in the literature:
  • a solid-phase approach ( WO 98/34111 )
  • multi-level process control ( WO 98/42673 ; Bioorganic and Medicinal Chemistry Lettetters Vol. 2, p. 371, 1992 ; Journal of Heterocyclic Chemistry Vol. 25, p. 1831, 1988 ; Journal of the Chemical Society, Perkin Transactions I (1989), page 2245 ) or
  • a Lewis acid catalyzed "one pot" method ( Journal of the Chemical Society, Chemical Communications, 1999, p. 651 ; Journal of the American Chemical Society, Vol. 118, p. 8977, 1996 ).
However, all of these methods clearly have some disadvantages.

Abweichend von diesen ist das hier beschriebene sog. Grundverfahren ein Trifluoressigsäure vermitteltes - vorzugsweise "Eintopf"- Verfahren, bei dem je eine aromatische Amin-, Aldehyd- und elektronenreiche Olefinkomponente miteinander reagieren.
In dem Grundverfahren werden substituierte 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivate gemäß Formel I hergestellt. Dabei werden Aniline gemäß Formel II,

Figure imgb0002
mit Glyoxylsäure gemäß Formel III und einem Benzofuran gemäß IV, in denen R1, R2, R3 und R4 unabhängig voneinander jeweils eine der bereits für Formel I angegebenen Bedeutungen haben oder mit einer Schutzgruppe versehen sind, mit Trifluoressigsäure zwischen 0°C und 100°C umgesetzt werden. Dabei ist es bevorzugt, daß die Reaktionsdauer 0.25 - 12 h, vorzugsweise maximal 2h, beträgt, die Reaktion bevorzugt bei Temperatur zwischen 20 und 40°C, vorzugsweise Raumtemperatur, erfolgt und/oder die Reaktion eine Eintopfreaktion ist.Deviating from these, the so-called basic process described here is a trifluoroacetic acid-mediated, preferably "one-pot" process in which one aromatic amine, one aldehyde and one electron-rich olefin component react with each other.
In the basic process, substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to formula I are prepared. Anilines according to formula II,
Figure imgb0002
 with glyoxylic acid according to formula III and a benzofuran according to IV, in which R 1 , R 2 , R 3 and R 4 each independently have one of the meanings already given for formula I or are provided with a protective group, with trifluoroacetic acid between 0 ° C and 100 ° C are implemented. It is preferred that the reaction time 0.25 - 12 h, preferably a maximum of 2h, the reaction preferably at a temperature between 20 and 40 ° C, preferably room temperature, takes place and / or the reaction is a one-pot reaction.

Ein entscheidender Vorteil des erfindungsgemäßen Verfahrens ist, daß das Verfahren gemäß einer Dominoreaktion (Iminbildung und nachgeschaltete Aza-Diels-Alder-Reaktion) sehr selektiv bei zudem guten Ausbeuten zu den gewünschten Systemen führt.
Ohne einen Knüpfungs- bzw. Abspaltungsschritt durchführen zu müssen, wie im Falle des solid phase-Ansatzes, ferner ohne Aufreinigung der Zwischenstufen - wie im Falle der beschriebenen Lösungschemie - unterscheidet sich das erfindungsgemäße Verfahren neben seiner einfachen Durchführbarkeit ferner durch seine Aufreinigungmethode. Durch mehrmaliges Waschen mit unpolaren Lösungsmitteln, wie beispielsweise n-Hexan lassen sich größtenteils die Produkte in hoher Reinheit erhalten. Anderenfalls gelingt ihre Aufreinigung mittels Säulenchromatographie. Insbesondere lassen sich Verbindungen der Formel I durch die Waschprozesse mit unpolaren Lösungsmitteln - wie beispielsweise nHexan - oder durch Kristallisation ihrer Salze diastereomerenrein erhalten.A decisive advantage of the process according to the invention is that the process according to a domino reaction (imine formation and downstream aza-Diels-Alder reaction) leads very selectively to the desired systems, in addition to good yields.
Without having to perform a knotting or cleavage step, as in the case of the solid phase approach, further without purification of the intermediates - as in the case of the described solution chemistry - the method of the invention differs in addition to its ease of operation also by its purification method. By repeated washing with non-polar solvents, such as n-hexane, for the most part, the products can be obtained in high purity. Otherwise, their purification succeeds by means of column chromatography. In particular, compounds of the formula I can be obtained diastereomerically pure by the washing processes with nonpolar solvents, such as, for example, n- hexane, or by crystallization of their salts.

Allgemein wird bei einer günstigen Form des Herstellungsverfahrens nach Abschluß der Bildung einer Verbindung nach Formel I die Verbindung mit einer Base oder Säure, die bereits das gewünschte Kation bzw. Anion enthalten kann, in Verbindung gebracht und das entstehende Salz anschließend gereinigt.
Die meisten der hier eingesetzten Reagenzien, insbesondere nach Formel II, III und IV sind käuflich zu erwerben oder können durch einfache, dem Fachmann bekannte Syntheseschritte hergestellt werden.Generally, in a convenient form of the preparation process, upon completion of the formation of a compound of formula I, the compound is contacted with a base or acid which may already contain the desired cation or anion, and the resulting salt is subsequently purified.
Most of the reagents used here, in particular according to formula II, III and IV are commercially available or can be prepared by simple, known in the art synthesis steps.

Unter vielen der genannten Reaktionsbedingungen können OH- SH und NH2-Gruppen möglicherweise unerwünschte Nebenreaktionen eingehen. Es ist daher bevorzugt, diese mit Schutzgruppen zu versehen oder im Falle von NH2 durch NO2 zu ersetzen und vor der Aufreinigung des Endprodukts die Schutzgruppe abzuspalten, bzw. die NO2-Gruppe zu reduzieren. Ein weiterer Gegenstand der Anmeldung ist daher eine Abwandlung der oben beschriebenen Verfahrens, bei dem in den Ausgangsverbindungen mindestens eine OH-Gruppe durch eine OSi(Ph)2tert-Butyl-Gruppe, mindestens eine SH-Gruppe durch eine S-p-Methoxybenzylgruppe und/oder mindestens eine NH2-Gruppe durch eine NO2-Gruppe ersetzt wurde und vor der Aufreinigung des Endprodukts mindestens eine - vorzugsweise alle - OSi(Ph)2tert-Butyl-Gruppe/n, mit Tetrabutylammoniumflluorid in Tetrahydrofuran und/oder mindestens eine - vorzugsweise alle - p-Methoxybenzylgruppe/n mit einem Metallamin, bevorzugt Natriumamin, abgespalten und/oder mindestens eine - vorzugsweise alle - NO2-Gruppe/n zu NH2 reduziert wird.
Weiter sind Carbonsäure- oder Thiocarbonsäure-Gruppen unter den genannten Reaktionsbedingungen unter Umständen nicht stabil, so daß es bevorzugt ist, deren Methylester in den Reaktionen einzusetzen und das Verfahrensprodukt anschließend mit KOH-Lösung bzw. NaOH-Lösung in Methanol bei 40°C - 60°C zu verseifen. Ein weiterer Gegenstand der Erfindung ist daher eine Abwandlung der oben beschriebenen Verfahren, in dem vor der Aufreinigung des Endprodukts ein Verfahrensprodukt mit mindestens einer C(O)OCH3- OC(O)OCH3- und/oder C(S)OCH3-Gruppe mit KOH-Lösung bzw. NaOH-Lösung in Methanol oder Ethanol bei 0°C - 100°C, vorzugsweise 40°C - 60°C, verseift wird.
Daher kann es auch günstig sein, zur Herstellung substituierter 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivate gemäß Formel I mit R5 = H für das Grundverfahren Ausgangsprodukte gemäß Formel III zu verwenden, in denen R5 ≠ H und R5 vorzugsweise Alkyl, insbesondere CH3 und C2H5 sind, einzusetzen. Nach dem Grundverfahren und auch den möglicherweise daran anschließenden Folgereaktionen wird das Reaktionsprodukt mit einer entsprechenden Base, vorzugsweise NaOH oder KOH, in Ethanol oder Methanol, bei Temperaturen zwischen O-100 °C, vorzugsweise 40°C - 60°C, verseift (Organikum, 1990, S. 418).Under many of the reaction conditions mentioned, OH-SH and NH 2 groups may possibly undergo undesirable side reactions. It is therefore preferred to provide these with protective groups or in the case of Replace NH 2 with NO 2 and, before purification of the final product, remove the protective group or reduce the NO 2 group. Another object of the application is therefore a modification of the method described above, wherein in the starting compounds at least one OH group by an OSi (Ph) 2 tert-butyl group, at least one SH group by a Sp-methoxybenzyl group and / or at least one NH 2 group has been replaced by a NO 2 group and before purification of the final product at least one - preferably all - OSi (Ph) 2 tert-butyl group / n, with tetrabutylammonium fluoride in tetrahydrofuran and / or at least one - preferably all - p-methoxybenzyl / n with a metal amine, preferably sodium, cleaved and / or at least one - preferably all - NO 2 group / n is reduced to NH 2 .
Further, carboxylic acid or thiocarboxylic acid groups under the reaction conditions mentioned may not be stable, so that it is preferred to use their methyl ester in the reactions and the process product then with KOH solution or NaOH solution in methanol at 40 ° C - 60 ° C to saponify. Another object of the invention is therefore a modification of the method described above, in which before the purification of the final product, a process product having at least one C (O) OCH 3 - OC (O) OCH 3 - and / or C (S) OCH 3 - Group with KOH solution or NaOH solution in methanol or ethanol at 0 ° C - 100 ° C, preferably 40 ° C - 60 ° C, saponified.
Therefore, it may also be advantageous for the preparation of substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylic acid derivatives according to formula I with R 5 = H for the basic process starting materials according to Use formula III, in which R 5 ≠ H and R 5 are preferably alkyl, in particular CH 3 and C 2 H 5 to use. After the basic process and also the possible subsequent reactions, the reaction product with a corresponding base, preferably NaOH or KOH, in ethanol or methanol, at temperatures between 0-100 ° C, preferably 40 ° C - 60 ° C, saponified (Organikum, 1990, p. 418).

Zur Herstellung der Salze insbesondere der physiologisch verträglichen Salze mit Kationen bzw. Basen wird wie folgt vorgegangen:
Ein Äquivalent einer Verbindung gemäß Formel I, vorzugsweise eine Iminosäure, bzw. eine Carbonsäure, insbesondere mit R3 = H, wird in wenig Wasser suspendiert und ein Äquivalent 1-normaler wäßriger Lauge, beispielsweise NaOH oder KOH, zugegeben. Bei schlechter Löslichkeit wird soviel Methanol zugetropft, bis vollständige Lösung eintritt. Nach Rühren bei Raumtemperatur wird im Rotationsverdampfer eingeengt, die verbliebene Lösung bei tiefen Temperaturen in einem Gemisch aus Isopropanol/Trockeneis eingefroren und gefriergetrocknet. Die Salze, insbesondere der Iminosäuren, bzw. Carbonsäuren, vorzugsweise die Natrium- oder Kaliumsalze, werden als meist farblose Feststoffe erhalten. Alternativ ist es auch möglich, die Kalium- bzw. Natriumsalze mit Kalium-bzw. Natriumtrimethylsilanolat herzustellen ( E.D. Laganis, B.L. Chenard; Tetrahedron Letters 25, 5831 - 5834 (1984 )). Kalium- bzw. Natriumtrimethylsilanolat wird dabei unter Stickstoff in einem organischen Lösungsmittel (z.B. Dichlormethan, Toluol, THF) gelöst und der Ester, bzw. die Säure, in einer Portion zugegeben. Das Reaktionsgemisch wird mehrere Stunden bei Raumtemperatur gerührt und abfiltriert. Der meist farblose Feststoff wird gewaschen und im Vakuum getrocknet. Die Kalium- bzw. Natriumsalze werden als Feststoffe erhalten.For the preparation of the salts, in particular of the physiologically tolerated salts with cations or bases, the procedure is as follows:
One equivalent of a compound according to formula I, preferably an imino acid, or a carboxylic acid, in particular with R 3 = H, is suspended in a little water and one equivalent of 1 normal aqueous alkali, for example NaOH or KOH, is added. With poor solubility, so much methanol is added dropwise until complete solution occurs. After stirring at room temperature, the mixture is concentrated in a rotary evaporator, the remaining solution is frozen at low temperatures in a mixture of isopropanol / dry ice and freeze-dried. The salts, in particular the imino acids, or carboxylic acids, preferably the sodium or potassium salts, are obtained as mostly colorless solids. Alternatively, it is also possible, the potassium or sodium salts with potassium or. To produce sodium trimethylsilanolate ( Ed Laganis, BL Chenard; Tetrahedron Letters 25, 5831-5834 (1984 )). Potassium or Natriumtrimethylsilanolat is thereby dissolved under nitrogen in an organic solvent (eg dichloromethane, toluene, THF) and the ester, or the acid added in one portion. The reaction mixture is stirred for several hours at room temperature and filtered off. The usually colorless solid is washed and dried in vacuo. The potassium or sodium salts are obtained as solids.

Die erfindungsgemäßen substituierten 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivate sind toxikologisch unbedenklich, so daß sie sich als pharmazeutischer Wirkstoff in Arzneimitteln eignen.The substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to the invention are toxicologically harmless, so that they are suitable as pharmaceutical active ingredient in medicaments.

Ein weiterer Gegenstand der Erfindung ist daher auch ein Arzneimittel enthaltend als Wirkstoff mindestens ein erfindungsgemäßes substituiertes 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivat gemäß Formel I in dargestellter Form oder in Form der Säure oder Base oder in Form seiner Salze, insbesondere der physiologisch verträglichen Salze, oder in Form seiner Solvate, insbesondere der Hydrate; insbesondere in Form seiner physiologisch verträglichen Salze mit Kationen oder Basen oder mit Anionen oder Säuren; gegebenenfalls in Form seiner Racemate, seiner reinen Stereoisomeren, insbesondere Enantiomeren oder Diastereomeren, oder in Form von Mischungen der Stereoisomeren, insbesondere der Enantiomeren oder Diastereomeren, in einem beliebigen Mischungsverhältnis; sowie gegebenenfalls enthaltend geeignete Zusatz-und/oder Hilfsstoffe und/oder gegebenenfalls weitere Wirkstoffe.Another object of the invention is therefore also a medicament containing as active ingredient at least one inventive substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to formula I in the form shown or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular of the hydrates; especially in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; and optionally containing suitable additives and / or adjuvants and / or optionally further active ingredients.

Die erfindungsgemäßen Arzneimittel können als flüssige Arzneiformen in Form von Injektionslösungen, Tropfen oder Säfte, als halbfeste Arzneiformen in Form von Granulaten, Tabletten, Pellets, Patches, Kapseln, Pflaster oder Aerosolen verabreicht werden und enthalten neben mindestens einem erfindungsgemäßen substituierten 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivat je nach galenischer Form gegebenenfalls Trägermaterialien Füllstoffe, Lösungsmittel, Verdünnungsmittel, Farbstoffe und/oder Bindemittel. Die Auswahl der Hilfsstoffe sowie die einzusetzenden Mengen derselben hängt davon ab, ob das Arzneimittel oral, peroral, parenteral, intravenös, intraperitoneal, intradermal, intramuskulär, intranasal, buccal, rectal oder örtlich, zum Beispiel auf Infektionen an der Haut, der Schleimhäute und an den Augen, appliziert werden soll. Für die orale Applikation eignen sich Zubereitungen in Form von Tabletten, Dragees, Kapseln, Granulaten, Tropfen, Säften und Sirupen, für die parenterale, topische und inhalative Applikation Lösungen, Suspensionen, leicht rekonstituierbare Trockenzubereitungen sowie Sprays. Erfindungsgemäße substituierte 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivate in einem Depot in gelöster Form oder in einem Pflaster, gegebenenfalls unter Zusatz von die Hautpenetration fördernden Mitteln, sind geeignete perkutane Applikationszubereitungen. Oral oder perkutan anwendbare Zubereitungsformen können die erfindungsgemäßen substituierten 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivate verzögert freisetzen. Die an den Patienten zu verabreichende Wirkstoffmenge variiert in Abhängigkeit vom Gewicht des Patienten, von der Applikationsart, der Indikation und dem Schweregrad der Erkrankung. Üblicherweise werden 2 bis 500 mg/kg wenigstens eines erfindungsgemäßen substituierten 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivats der Formel I appliziert.The medicaments according to the invention can be administered as liquid dosage forms in the form of injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, patches or aerosols and in addition to at least one substituted 5,6,6a according to the invention, 11b-Tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative, depending on the galenic form, optionally carrier materials, fillers, solvents, diluents, dyes and / or binders. The choice of excipients and the amounts to be used depend on whether the drug is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or topical, for example on skin infections, mucous membranes and on the eyes, to be applied. For oral administration, preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable, for parenteral, topical and inhalative administration solutions, suspensions, readily reconstitutable dry preparations and sprays. Substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to the invention in a depot in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents suitable percutaneous application preparations. Orally or percutaneously applicable preparation forms can release the substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to the invention with a delay. The amount of active substance to be administered to the patient varies depending on the patient Weight of the patient, the mode of administration, the indication and the severity of the disease. Usually, 2 to 500 mg / kg of at least one substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the formula I according to the invention are applied.

Vorzugsweise werden die erfindungsgemäßen substituierten 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivate zur Schmerzbehandlung, insbesondere chronischer und neuropathischer Schmerzen, aber auch bei Migräne eingesetzt, so daß ein weiterer Erfindungsgegenstand die Verwendung mindestens eines erfindungsgemäßen substituierten 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivats gemäß Formel I in dargestellter Form oder in Form der Säure oder Base oder in Form seiner Salze, insbesondere der physiologisch verträglichen Salze, oder in Form seiner Solvate, insbesondere der Hydrate; insbesondere in Form seiner physiologisch verträglichen Salze mit Kationen oder Basen oder mit Anionen oder Säuren; gegebenenfalls in Form seiner Racemate, seiner reinen Stereoisomeren, insbesondere Enantiomeren oder Diastereomeren, oder in Form von Mischungen der Stereoisomeren, insbesondere der Enantiomeren oder Diastereomeren, in einem beliebigen Mischungsverhältnis; zur Herstellung eines Arzneimittels zur Behandlung von Schmerz, insbesondere des neuropathischen und/oder chronischen Schmerzes, und/oder zur Behandlung von Migräne ist.The substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivatives according to the invention are preferably used for the treatment of pain, in particular chronic and neuropathic pain, but also in migraine, so that a Another subject of the invention is the use of at least one substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative according to the invention of formula I in the form shown or in the form of the acid or base or in In the form of its salts, in particular of the physiologically tolerated salts, or in the form of its solvates, in particular hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment of pain, in particular neuropathic and / or chronic pain, and / or for the treatment of migraine.

Aus der Affinität an den NMDA-Rezeptor ergeben sich weitere Anwendungsgebiete, da NMDA-Antagonisten bekanntermaßen u.a. eine neuroprotektive Wirkung haben und daher auch gut bei mit Neurodegeneration und -schädigung einhergehenden Krankheitsbildern, wie Morbus Parkinson und Morbus Huntington etc. eingesetzt werden können. Weitere Indikationen der erfindungsgemäßen NMDA-Antagonisten sind Epilepsie, Glaukom, Osteoporose, Ototoxizität, die mit Alkohol- und/oder Drogenmißbrauch einhergehenden Entzugserscheinungen, der Schlaganfall, sowie damit zusammenhängend cerebrale Ischämien, cerebrale Infarkten, Hirnödem, Hypoxie, Anoxie, sowie auch der Einsatz zur Anxiolyse und in der Anästhesie. Ein weiterer Gegenstand der Erfindung ist daher die Verwendung mindestens eines erfindungsgemäßen substituierten 5,6,6a, 11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivats gemäß Formel I; in dargestellter Form oder in Form der Säure oder Base oder in Form seiner Salze, insbesondere der physiologisch verträglichen Salze, oder in Form seiner Solvate, insbesondere der Hydrate; insbesondere in Form seiner physiologisch verträglichen Salze mit Kationen oder Basen oder mit Anionen oder Säuren; gegebenenfalls in Form seiner Racemate, seiner reinen Stereoisomeren, insbesondere Enantiomeren oder Diastereomeren, oder in Form von Mischungen der Stereoisomeren, insbesondere der Enantiomeren oder Diastereomeren, in einem beliebigen Mischungsverhältnis; zur Herstellung eines Arzneimittels zur Behandlung/Prophylaxe von/bei Epilepsie, Morbus Parkinson, Morbus Huntington, Glaukom, Ototoxizität, Entzugserscheinungen bei Alkohol-und/oder Drogenmißbrauch, Schlaganfall, cerebralen Ischämien, cerebralen Infarkten, Hirnödem, Hypoxie, Anoxie und/oder zur Anxiolyse und/oder Anästhesie.From the affinity to the NMDA receptor, there are further fields of application, since NMDA antagonists are known to have inter alia a neuroprotective effect and therefore can also be used well in neurodegeneration and damage-associated diseases, such as Parkinson's disease and Huntington's disease, etc. Further indications of the NMDA antagonists according to the invention are epilepsy, glaucoma, osteoporosis, ototoxicity, the withdrawal symptoms associated with alcohol and / or drug abuse, the stroke, and related cerebral ischaemias, cerebral infarctions, cerebral edema, hypoxia, anoxia, as well as anxiolysis and anesthesia. Another object of the invention is therefore the use of at least one substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the formula I according to the invention; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment / prophylaxis of epilepsy, Parkinson's disease, Huntington's disease, glaucoma, ototoxicity, withdrawal symptoms in alcohol and / or drug abuse, stroke, cerebral ischaemias, cerebral infarctions, cerebral edema, hypoxia, anoxia and / or anxiolysis and / or anesthesia.

Überraschenderweise hat es sich herausgestellt, daß die erfindungsgemäßen substituierten 1,2,3,4-Tetrahydrochinolin-2-carbonsäurederivats auch für weitere Indikationen, insbesondere zur Behandlung von Harninkontinenz, Juckreiz, Tinnitus aurium und/oder Diarrhoe sehr geeignet sind. Ein weiterer Gegenstand der Anmeldung ist daher die Verwendung mindestens eines erfindungsgemäßen substituierten 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivats gemäß Formel I; in dargestellter Form oder in Form der Säure oder Base oder in Form seiner Salze, insbesondere der physiologisch verträglichen Salze, oder in Form seiner Solvate, insbesondere der Hydrate; insbesondere in Form seiner physiologisch verträglichen Salze mit Kationen oder Basen oder mit Anionen oder Säuren; gegebenenfalls in Form seiner Racemate, seiner reinen Stereoisomeren, insbesondere Enantiomeren oder Diastereomeren, oder in Form von Mischungen der Stereoisomeren, insbesondere der Enantiomeren oder Diastereomeren, in einem beliebigen Mischungsverhältnis; zur Herstellung eines Arzneimittels zur Behandlung von Harninkontinenz, Juckreiz, Tinnitus aurium und/oder DiarrhoeSurprisingly, it has been found that the substituted 1,2,3,4-tetrahydroquinoline-2-carboxylic acid derivative of the invention are also very suitable for other indications, in particular for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea. A further subject of the application is therefore the use of at least one substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the formula I according to the invention; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the manufacture of a medicament for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea

Aber auch in andereren Indikationen sind die erfindungsgemäßen Verbindungen wirksam. Ein weiterer Gegenstand der Anmeldung ist daher die Verwendung mindestens eines erfindungsgemäßen substituierten 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivats gemäß Formel I; in dargestellter Form oder in Form der Säure oder Base oder in Form seiner Salze, insbesondere der physiologisch verträglichen Salze, oder in Form seiner Solvate, insbesondere der Hydrate; insbesondere in Form seiner physiologisch verträglichen Salze mit Kationen oder Basen oder mit Anionen oder Säuren; gegebenenfalls in Form seiner Racemate, seiner reinen Stereoisomeren, insbesondere Enantiomeren oder Diastereomeren, oder in Form von Mischungen der Stereoisomeren, insbesondere der Enantiomeren oder Diastereomeren, in einem beliebigen Mischungsverhältnis; zur Herstellung eines Arzneimittels zur Behandlung/Prophylaxe von/bei Schizophrenie, Morbus Alzheimer, Psychosen bedingt durch erhöhten Aminosäurespiegel, AIDS-Demens, Encephalomyelitis, Tourette-Syndrom, perinataler Asphyxie inflammatorischen und allergischen Reaktionen, Depressionen, Drogen-und/oder Alkoholmißbrauch, Gastritis, Diabetes, cardiovaskulären Erkrankungen, Atemwegserkrankungen, Husten und/oder seelischen Erkrankungen.But in other indications, the compounds of the invention are effective. A further subject of the application is therefore the use of at least one substituted 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid derivative of the formula I according to the invention; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; for the preparation of a medicament for the treatment / prophylaxis of schizophrenia, Alzheimer's disease, psychoses due to increased levels of amino acids, AIDS dementia, encephalomyelitis, Tourette's syndrome, perinatal asphyxia, inflammatory and allergic reactions, depression, drug and / or alcohol abuse, gastritis, Diabetes, cardiovascular diseases, respiratory diseases, cough and / or mental illness.

Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur Behandlung eines nichthumanen Säugetieres oder Menschen, das oder der eine Behandlung medizinisch relevanter Symptome benötigt, durch Verabreichung einer therapeutisch wiksamen Dosis eines erfindungsgemäßen substituierten 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäurederivats gemäß Formel I; in dargestellter Form oder in Form der Säure oder Base oder in Form seiner Salze, insbesondere der physiologisch verträglichen Salze, oder in Form seiner Solvate, insbesondere der Hydrate; insbesondere in Form seiner physiologisch verträglichen Salze mit Kationen oder Basen oder mit Anionen oder Säuren; gegebenenfalls in Form seiner Racemate, seiner reinen Stereoisomeren, insbesondere Enantiomeren oder Diastereomeren, oder in Form von Mischungen der Stereoisomeren, insbesondere der Enantiomeren oder Diastereomeren, in einem beliebigen Mischungsverhältnis; oder eines erfindungsgemäßen Arzneimittels. Die Erfindung betrifft insbesondere entsprechende Verfahren zur Behandlung von Schmerz, insbesondere von neuropathischem und/oder chronischem Schmerz und/oder zur Behandlung von Migräne zur Behandlung von Harninkontinenz, Juckreiz, Tinnitus aurium und/oder Diarrhoe, zur Behandlung/Prophylaxe von/bei Epilepsie, Morbus Parkinson, Morbus Huntington, Glaukom, Osteoporose, Ototoxizität, Entzugserscheinungen bei Alkohol- und/oder Drogenmißbrauch, Schlaganfall, cerebralen Ischämien, cerebralen Infarkten, Hirnödem, Hypoxie, Anoxie und/oder zur Anxiolyse und/oder Anästhesie oder zur Behandlung/Prophylaxe von/bei Schizophrenie, Morbus Alzheimer, Psychosen bedingt durch erhöhten Aminosäurespiegel, AIDS-Demens, Encephalomyelitis, Tourette-Syndrom, perinataler Asphyxie inflammatorischen und allergischen Reaktionen, Depressionen, Drogen-und/oder Alkoholmißbrauch, Gastritis, Diabetes, cardiovaskulären Erkrankungen, Atemwegserkrankungen, Husten und/oder seelischen Erkrankungen.
Im folgenden wird die Erfindung weiter durch Beispiele erläutert, ohne sie darauf zu beschränken.Another object of the invention is a method of treating a non-human mammal or human that requires treatment of medically relevant symptoms by administering a therapeutically significant dose of a substituted 5,6,6a, 11b-tetrahydro-7-oxa-5 of the invention aza-benzo [c] fluorene-6-carboxylic acid derivative according to formula I; in the illustrated form or in the form of the acid or base or in the form of its salts, in particular of the physiologically tolerable salts, or in the form of its solvates, in particular the hydrates; in particular in the form of its physiologically acceptable salts with cations or bases or with anions or acids; optionally in the form of its racemates, its pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular the enantiomers or diastereomers, in any mixing ratio; or a drug of the invention. The invention particularly relates to corresponding methods for the treatment of pain, in particular of neuropathic and / or chronic pain and / or for the treatment of migraine for the treatment of urinary incontinence, itching, tinnitus aurium and / or diarrhea, for the treatment / prophylaxis of / in epilepsy, for morbus Parkinson's disease, Huntington's disease, glaucoma, osteoporosis, ototoxicity, withdrawal symptoms in alcohol and / or drug abuse, stroke, cerebral ischaemias, cerebral infarctions, cerebral edema, hypoxia, anoxia and / or anxiolysis and / or anesthesia or for the treatment / prophylaxis of / at Schizophrenia, Alzheimer's disease, psychosis due to elevated levels of amino acids, AIDS dementia, encephalomyelitis, Tourette's syndrome, perinatal asphyxia inflammatory and allergic reactions, depression, drug and / or alcohol abuse, gastritis, diabetes, cardiovascular disease, respiratory disease, cough and / or mental illness.
In the following, the invention will be further illustrated by examples without being limited thereto.

BeispieleExamples

Die folgenden Beispiele zeigen erfindungsgemäße Verbindungen sowie deren Darstellung und mit diesen durchgeführte Wirksamkeitsuntersuchungen.The following examples show compounds of the invention as well as their presentation and efficacy studies conducted therewith.

Dabei gelten generell folgende Angaben:
Die eingesetzten Chemikalien und Lösungsmittel wurden kommerziell bei den herkömmlichen Anbietern erworben (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCl etc.) oder werden nach allgemeinen, dem Fachmann bekannten Herstellungsverfahren synthetisiert. Insbesondere werden einige der Benzofurane, aber auch andere eingesetzte Verbindungen vor der unten beschriebenen Grundsynthese als Synthesebausteine nach bekannten Synthesevorschriften synthetisiert.
Die dünschichtchromatographischen Untersuchungen wurden mit HPTLC-Fertigplatten, Kieselgel 60 F 254, der Firma E. Merck, Darmstadt, durchgeführt.
Die Ausbeuten der hergestellten Verbindungen sind nicht optimiert.The following information generally applies:
The chemicals and solvents used have been commercially obtained from the traditional suppliers (Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCl, etc.) or are synthesized according to general manufacturing methods known to those skilled in the art. In particular, some of the benzofurans, but also other compounds used are synthesized prior to the basic synthesis described below as synthesis building blocks according to known synthesis instructions.
The dünschichtchromatographischen investigations were carried out with HPTLC ready plates, Kieselgel 60 F 254, E. Merck, Darmstadt.
The yields of the compounds produced are not optimized.

Die Analytik erfolgte über ESI-Massenspektroskopie.The analysis was carried out by ESI mass spectrometry.

Die Verbindungen sind numeriert, wobei die Angabe in Klammem grundsätzlich der Nummer der zugeordneten Verbindung entspricht.The connections are numbered, whereby the indication in brackets always corresponds to the number of the assigned connection.

Beispiel 0Example 0 Grundverfahrenbasic processing

  1. a) Je ein Äquivalent Anilinderivat und Trifluoressigsäure werden unter Rühren bei Raumtemperatur in 6 ml/mmol Acetonitril gelöst und anschließend 1,1 Äquivalente Ethylglyoxalat (50 % in Toluol) bzw. 1,1 Äquivalente Glyoxalsäuremonohydrat zugegeben. Nach zehn Minuten werden hierzu 3 Äquivalente der Benzofuran-Komponente zugesetzt und der Verlauf der Reaktion durch Dünnschichtchromatographie verfolgt (Laufmittelsystem Diethylether / Hexan, 1:1). Die Reaktion ist nach 2 Stunden beendet (DC-Kontrolle). Der Reaktionsansatz wird mit einem Überschuß an gesättigter, wäßriger Natriumhydrogencarbonat-Lösung versetzt und die organische Phase drei Mal mit Diethylether extrahiert. Die organische Phase wird mit Wasser neutral gewaschen, über Magnesiumsulfat getrocknet, abfiltriert, mit Diethylether gewaschen und nach Einengen durch Umkristallisation bzw. Kieselgel-Chromatographie isoliert. Die Charakterisierung der 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäureester erfolgt durch ESI-Massenspektrometrie. a) One equivalent of aniline derivative and trifluoroacetic acid are dissolved with stirring at room temperature in 6 ml / mmol acetonitrile and then 1.1 equivalents of ethyl glyoxalate (50% in toluene) or 1.1 equivalents Glyoxalsäuremonohydrat added. After ten minutes, 3 equivalents of the benzofuran component are added thereto and the course of the reaction is monitored by thin-layer chromatography (eluent system diethyl ether / hexane, 1: 1). The reaction is complete after 2 hours (TLC control). The reaction mixture is treated with an excess of saturated, aqueous sodium bicarbonate solution and the organic phase extracted three times with diethyl ether. The organic phase is washed neutral with water, over Dried magnesium sulfate, filtered off, washed with diethyl ether and isolated after concentration by recrystallization or silica gel chromatography. The characterization of the 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid esters is carried out by ESI mass spectrometry.
  2. b) Optionale anschließende Darstellung der freien 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäuren.
    Der zuvor beschriebene 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäureester (1 Äquivalent) wird in 4 ml/mmol Ethanol gelöst und unter Rühren bei Raumtemperatur mit 1,2 Äquivalenten wässriger 6N Natronlauge versetzt. Der Verlauf der Ester-Verseifung wird durch Dünnschichtchromatographie verfolgt (Laufmittelsystem Diethylether /Hexan, 1:1) und ist nach 30 Minuten beendet (DC-Kontrolle). Das Reaktionsgemisch wird am Rotationsverdampfer eingeengt, in ca. 10 ml Wasser aufgenommen und mit 32 %-iger HCl auf pH 1 eingestellt. Die wäßrige Lösung wird fünf Mal mit Diethylether extrahiert und nach Trocknen über Magnesiumsulfat eingeengt.     b) Optional subsequent presentation of the free 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acids.
    The above-described 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ester (1 equivalent) is dissolved in 4 ml / mmol of ethanol and stirred at room temperature with 1, 2 equivalents of aqueous 6N sodium hydroxide added. The course of the ester saponification is monitored by thin layer chromatography (eluent system diethyl ether / hexane, 1: 1) and is complete after 30 minutes (TLC control). The reaction mixture is concentrated on a rotary evaporator, taken up in about 10 ml of water and adjusted to pH 1 with 32% HCl. The aqueous solution is extracted five times with diethyl ether and concentrated after drying over magnesium sulfate.
Automatisiertes VerfahrenAutomated procedure

Ein Rundbodenröhrchen aus Glas (Durchmesser 16 mm, Länge 125 mm) mit Gewinde wurde mit einem Rührer versehen und mit einem Schraubdeckel mit Septum verschlossen. Das Röhrchen wurde in den auf 20 °C temperierten Rührblock gestellt. Anschließend wurden nacheinander die folgenden Reagenzien hinzupipettiert:

  • 1 ml einer Lösung aus Trifluoressigsäure, 0,1 M, und Anilinkomponente, 0,1 M, in Acetonitril;
  • 1 ml einer 0,11 M Lösung des Aldehyds in Acetonitril;
  • 1 ml einer 0,3 M Lösung des Benzofurans in Acetonitril.
A round-bottomed tube of glass (diameter 16 mm, length 125 mm) with thread was provided with a stirrer and sealed with a screw cap with septum. The tube was placed in the tempered at 20 ° C agitator. Subsequently, the following reagents were successively pipetted:
  • 1 ml of a solution of trifluoroacetic acid, 0.1 M, and aniline component, 0.1 M, in acetonitrile;
  • 1 ml of a 0.11 M solution of the aldehyde in acetonitrile;
  • 1 ml of a 0.3 M solution of benzofuran in acetonitrile.

Dabei ist hier unter Aldehyd sowohl die Glyoxalsäure als auch der Glyoxalester, vorzugsweise der Alkylester, insbesondere der Ethyl- oder Methylester, zu verstehen. Das Reaktionsgemisch wurde bei 20 °C in einem der Rührblöcke 10 h lang gerührt. Danach wurde die Reaktionslösung abfiltriert. Das Röhrchen wurde dabei zweimal mit je 1,5 ml, einer 7,5% NaHCO3-Lösung gespült.
Das Reaktionsgemisch wurde auf einem Vortexer mit 2 ml Ethylacetat versetzt und geschüttelt. Zur Ausbildung der Phasengrenze wurde in der Zentrifuge kurz zentrifugiert. Die Phasengrenze wurde optisch detektiert und die organische Phase abpipettiert. Im nächsten Schritt wurde die wäßrige Phase erneut mit 2 ml Ethylacetat versetzt, geschüttelt, zentrifugiert und die organische Phase abpipettiert. Die vereinigten organischen Phasen wurden über 2,4 g MgSO4 (granuliert) getrocknet. Das Lösungsmittel wurde in einer Vakuumzentrifuge entfernt.
Die Charakterisierung der freien 5,6,6a,11b-Tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure oder des -esters erfolgt durch ESI-Massenspektrometrie.Here, among aldehyde, both the glyoxylic acid and the glyoxal ester, preferably the alkyl ester, in particular the ethyl or Methyl ester, to understand. The reaction mixture was stirred at 20 ° C in one of the stirring blocks for 10 h. Thereafter, the reaction solution was filtered off. The tube was rinsed twice with 1.5 ml each of a 7.5% NaHCO 3 solution.
The reaction mixture was added to a vortexer with 2 ml of ethyl acetate and shaken. To form the phase boundary was briefly centrifuged in the centrifuge. The phase boundary was optically detected and the organic phase was pipetted off. In the next step, the aqueous phase was added again with 2 ml of ethyl acetate, shaken, centrifuged and the organic phase was pipetted off. The combined organic phases were dried over 2.4 g MgSO 4 (granulated). The solvent was removed in a vacuum centrifuge.
Characterization of the free 5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid or ester is carried out by ESI mass spectrometry.

Grundsätzlich kann sich bei Verbindungen mit R3 ≠ H sowohl nach automatisierten wie normalem Grundverfahren eine Verseifung nach dem Fachmann bekannten Methoden anschliessen, so beispielsweise mit KOH-Lösung bzw. NaOH-Lösung in Methanol oder Ethanol bei 0°C - 100°C, vorzugsweise 40°C - 60°C.In principle, in the case of compounds with R 3 ≠ H, saponification can be carried out by methods known to the person skilled in the art both using an automated and normal basic method, for example with KOH solution or NaOH solution in methanol or ethanol at 0 ° C.-100 ° C., preferably 40 ° ° C - 60 ° C.

Beispiel 1example 1

Figure imgb0003
Figure imgb0003

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (1)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 1 )

Verbindung 1 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und dem unsubstituierten Benzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 1 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and the unsubstituted benzofuran, wherein the resulting ester was finally saponified.

Beispiel 2Example 2

Figure imgb0004
Figure imgb0004

1,3-Dichlor-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (2)1,3-dichloro-10-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 2 )

Verbindung 2 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 5-Methoxybenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 2 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 5-methoxybenzofuran, wherein the resulting ester was finally saponified.

Beispiel 3Example 3

Figure imgb0005
Figure imgb0005

1,3-Dichlor-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (3)1,3-dichloro-8-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 3 )

Verbindung 3 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 7-Methylbenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 3 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-methylbenzofuran, wherein the resulting ester was finally saponified.

Beispiel 4Example 4

Figure imgb0006
Figure imgb0006

1,3-Dichlor-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (4)1,3-dichloro-8-ethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 4 )

Verbindung 4 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 7-Ethylbenzofuran hergestellt wobei der entstehende Ester abschließend verseift wurde.Compound 4 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-ethylbenzofuran wherein the resulting ester was finally saponified.

Beispiel 5Example 5

Figure imgb0007
Figure imgb0007

1,3-Dichlor-8-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (5)1,3-dichloro-8-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 5 )

Verbindung 5 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 7-Methoxybenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 5 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-methoxybenzofuran, wherein the resulting ester was finally saponified.

Beispiel 6Example 6

Figure imgb0008
Figure imgb0008

1,3-Dichlor-8-fluor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (6)1,3-dichloro-8-fluoro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 6 )

Verbindung 6 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 7-Fluorbenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 6 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-fluorobenzofuran, wherein the resulting ester was finally saponified.

Beispiel 7Example 7

Figure imgb0009
Figure imgb0009

1,3,8-Trichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (7)1,3,8-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 7 )

Verbindung 7 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 7-Chlorbenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 7 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-chlorobenzofuran, wherein the resulting ester was finally saponified.

Beispiel 8Example 8

Figure imgb0010
Figure imgb0010

8-Brom-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (8)8-bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 8 )

Verbindung 8 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 7-Brombenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 8 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-bromobenzofuran, wherein the resulting ester was finally saponified.

Beispiel 9Example 9

Figure imgb0011
Figure imgb0011

8-Iod-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (9)8-iodo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 9 )

Verbindung 9 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 7-Iodbenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 9 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 7-iodobenzofuran, wherein the resulting ester was finally saponified.

Beispiel 10Example 10

Figure imgb0012
Figure imgb0012

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6,8-dicarbonsäure (10)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6,8-dicarboxylic acid ( 10 )

Verbindung 10 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und Benzofuran-7-carbonsäure hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 10 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and benzofuran-7-carboxylic acid, wherein the resulting ester was finally saponified.

Beispiel 11Example 11

Figure imgb0013
Figure imgb0013

1,3-Dichlor-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (11)1,3-dichloro-10-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 11 )

Verbindung 11 nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und dem 5-Methylbenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 11 was prepared according to the basic method of Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and the 5-methylbenzofuran, wherein the resulting ester was finally saponified.

Beispiel 12Example 12

Figure imgb0014
Figure imgb0014

1,3-Dichlor-10-fluor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (12)1,3-dichloro-10-fluoro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 12 )

Verbindung 12 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 5-Fluorbenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 12 was prepared according to the basic method of Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 5-fluorobenzofuran, wherein the resulting ester was finally saponified.

Beispiel 13Example 13

Figure imgb0015
Figure imgb0015

1,3,10-Trichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (13)1,3,10-Trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 13 )

Verbindung 13 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 5-Chlorbenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 13 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 5-chlorobenzofuran, wherein the resulting ester was finally saponified.

Beispiel 13Example 13

Figure imgb0016
Figure imgb0016

10-Brom-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (14)10-Bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 14 )

Verbindung 14 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und dem 5-Brombenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 14 was prepared by the basic method of Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and the 5-bromobenzofuran, wherein the resulting ester was finally saponified.

Beispiel 14Example 14

Figure imgb0017
Figure imgb0017

10-Iod-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (15)10-Iodo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 15 )

Verbindung 15 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, dem Glyoxalsäureethylester und dem 5-Iodbenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 15 was prepared by the basic method of Example 0 from 3,5-dichloroaniline, the ethyl glyoxalate and the 5-iodobenzofuran, wherein the resulting ester was finally saponified.

Beispiel 16Example 16

Figure imgb0018
Figure imgb0018

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6,10-dicarbonsäure (16)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6,10-dicarboxylic acid ( 16 )

Verbindung 16 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und Benzofuran-5-carbonsäure hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 16 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and benzofuran-5-carboxylic acid, wherein the resulting ester was finally saponified.

Beispiel 17Example 17

Figure imgb0019
Figure imgb0019

1,3-Dichlor-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure (17)1,3-dichloro-10-cyano-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid ( 17 )

Verbindung 17 wurde nach dem Grundverfahren nach Beispiel 0 aus 3,5-Dichloranilin, Glyoxalsäureethylester und 5-Cyanobenzofuran hergestellt, wobei der entstehende Ester abschließend verseift wurde.Compound 17 was prepared by the basic method according to Example 0 from 3,5-dichloroaniline, ethyl glyoxalate and 5-cyanobenzofuran, wherein the resulting ester was finally saponified.

Beispiel 18: Allgemeine Darstellung der Salze mit Kationen am Beispiel der Verbindungen gemäß einem der Beispiele 1-17.Example 18: General presentation of the salts with cations using the example of the compounds according to one of Examples 1-17.

Ein Äquivalent der Verbindung gemäß einem der Beispiele 1 bis 17, vorzugsweise eine Iminosäure, wird in wenig Wasser suspendiert und ein Äquivalent 1-normaler wäßriger Lauge, vorzugsweise NaOH oder KOH, zugegeben. Bei schlechter Löslichkeit wird soviel Methanol zugetropft, bis vollständige Lösung eintritt. Nach 30 Minuten Rühren bei Raumtemperatur wird im Rotationsverdampfer eingeengt, die verbliebene Lösung bei - 60°C in einem Gemisch aus Isopropanol/Trockeneis eingefroren und gefriergetrocknet. Die Salze, insbesondere der Iminosäuren, vorzugsweise die Natrium- oder Kaliumsalze, werden als meist farblose Feststoffe erhalten.One equivalent of the compound according to any one of Examples 1 to 17, preferably an imino acid, is suspended in a little water and one equivalent of 1 normal aqueous alkali, preferably NaOH or KOH, is added. With poor solubility, so much methanol is added dropwise until complete solution occurs. After stirring for 30 minutes at room temperature, the mixture is concentrated in a rotary evaporator, the remaining solution is frozen at -60 ° C. in a mixture of isopropanol / dry ice and freeze-dried. The salts, in particular the imino acids, preferably the sodium or potassium salts are obtained as mostly colorless solids.

Alternativ ist es auch möglich, die Kalium- bzw. Natriumsalze mit Kalium-bzw. Natriumtrimethylsilanolat herzustellen ( E.D. Laganis, B.L. Chenard; Tetrahedron Letters 25, 5831 - 5834 (1984 )). Kalium- bzw. Natriumtrimethylsilanolat wird unter Stickstoff in einem organischen Lösungsmittel (Dichlormethan, Toluol, THF) gelöst und der Ester, bzw. die Säure, in einer Portion zugegeben. Das Reaktionsgemisch wird vier Stunden bei Raumtemperatur gerührt und abfiltriert. Der meist farblose Feststoff wird mit Diethylether gewaschen und im Vakuum getrocknet. Die Kalium- bzw. Natriumsalze werden als Feststoffe erhalten.Alternatively, it is also possible, the potassium or sodium salts with potassium or. To produce sodium trimethylsilanolate ( Ed Laganis, BL Chenard; Tetrahedron Letters 25, 5831-5834 (1984 )). Potassium or Natriumtrimethylsilanolat is dissolved under nitrogen in an organic solvent (dichloromethane, toluene, THF) and the ester, or acid, added in one portion. The reaction mixture is stirred for four hours at room temperature and filtered off. The usually colorless solid is washed with diethyl ether and dried in vacuo. The potassium or sodium salts are obtained as solids.

Die Verbindungen gemäß Beispiel 19 bis 35 sind nach diesen beispielhaften Vorschriften hergestellte Natriumsalze der Verbindungen 1 bis 17, die Verbindungen gemäß Beispielen 36 bis 52 die entsprechend hergestellten Kaliumsalze.The compounds according to Examples 19 to 35 are sodium salts of compounds 1 to 17 prepared by these exemplary procedures, the compounds according to Examples 36 to 52 the correspondingly prepared potassium salts.

Beispiel 19Example 19

Figure imgb0020
Figure imgb0020

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (19)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 19 )

Verbindung 19 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 1 hergestellt.Compound 19 was prepared by the method of Example 18 from Compound 1 .

Beispiel 20Example 20

Figure imgb0021
Figure imgb0021

1,3-Dichlor-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (20)1,3-dichloro-10-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 20 )

Verbindung 20 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 2 hergestellt.Compound 20 was prepared by the method of Example 18 from Compound 2 .

Beispiel 21Example 21

Figure imgb0022
Figure imgb0022

1,3-Dichlor-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (21)1,3-dichloro-8-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 21 )

Verbindung 21 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 3 hergestellt.Compound 21 was prepared by the method of Example 18 from Compound 3 .

Beispiel 22Example 22

Figure imgb0023
Figure imgb0023

1,3-Dichlor-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (22)1,3-dichloro-8-ethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 22 )

Verbindung 22 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 4 hergestellt.Compound 22 was prepared by the method of Example 18 from compound 4 .

Beispiel 23Example 23

Figure imgb0024
Figure imgb0024

1,3-Dichlor-8-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (23)1,3-dichloro-8-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 23 )

Verbindung 23 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 5 hergestellt.Compound 23 was prepared by the method of Example 18 from compound 5 .

Beispiel 24Example 24

Figure imgb0025
Figure imgb0025

1,3-Dichlor-8-fluor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (24)1,3-dichloro-8-fluoro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 24 )

Verbindung 24 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 6 hergestellt.Compound 24 was prepared by the method of Example 18 from Compound 6 .

Beispiel 25Example 25

Figure imgb0026
Figure imgb0026

1,3,8-Trichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (25)1,3,8-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 25 )

Verbindung 25 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 7 hergestellt.Compound 25 was prepared by the method of Example 18 from Compound 7 .

Beispiel 261Example 261

Figure imgb0027
Figure imgb0027

8-Brom-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (26)8-bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 26 )

Verbindung 26 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 8 hergestellt.Compound 26 was prepared by the method of Example 18 from compound 8 .

Beispiel 27Example 27

Figure imgb0028
Figure imgb0028

8-Iod-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (27)8-iodo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 27 )

Verbindung 27 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 9 hergestellt.Compound 27 was prepared by the method of Example 18 from compound 9 .

Beispiel 28Example 28

Figure imgb0029
Figure imgb0029

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6,8-dicarboxylat; Dinatriumsalz (28)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6,8-dicarboxylate; Disodium salt ( 28 )

Verbindung 28 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 10 hergestellt.Compound 28 was prepared by the method of Example 18 from Compound 10 .

Beispiel 29Example 29

Figure imgb0030
Figure imgb0030

1,3-Dichlor-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (29)1,3-dichloro-10-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 29 )

Verbindung 29 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 11 hergestellt.Compound 29 was prepared by the method of Example 18 from compound 11 .

Beispiel 30Example 30

Figure imgb0031
Figure imgb0031

1,3-Dichlor-10-fluor 5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (30)1,3-dichloro-10-fluoro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylate; Sodium salt ( 30 )

Verbindung 30 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 12 hergestellt.Compound 30 was prepared by the method of Example 18 from compound 12 .

Beispiel 31Example 31

Figure imgb0032
Figure imgb0032

1,3,10-Trichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (31)1,3,10-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 31 )

Verbindung 31 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 13 hergestellt.Compound 31 was prepared by the method of Example 18 from Compound 13 .

Beispiel 32Example 32

Figure imgb0033
Figure imgb0033

10-Brom-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (32)10-bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 32 )

Verbindung 32 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 14 hergestellt.Compound 32 was prepared by the method of Example 18 from Compound 14 .

Beispiel 33Example 33

Figure imgb0034
Figure imgb0034

10-Iod-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (33)10-iodo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 33 )

Verbindung 33 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 15 hergestellt.Compound 33 was prepared by the method of Example 18 from Compound 15 .

Beispiel 34Example 34

Figure imgb0035
Figure imgb0035

1,3-Dichior-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6,10-dicarboxylat; Dinatriumsalz (34)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6,10-dicarboxylate; Disodium salt ( 34 )

Verbindung 34 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 16 hergestellt.Compound 34 was prepared by the method of Example 18 from Compound 16 .

Beispiel 35Example 35

Figure imgb0036
Figure imgb0036

1,3-Dichlor-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Natriumsalz (35)1,3-dichloro-10-cyano-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Sodium salt ( 35 )

Verbindung 35 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 17 hergestellt.Compound 35 was prepared by the method of Example 18 from Compound 17 .

Beispiel 36Example 36

Figure imgb0037
Figure imgb0037

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (36)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 36 )

Verbindung 36 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 1 hergestellt.Compound 36 was prepared by the method of Example 18 from Compound 1 .

Beispiel 37Example 37

Figure imgb0038
Figure imgb0038

1,3-Dichlor-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (37)1,3-dichloro-10-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 37 )

Verbindung 37 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 2 hergestellt.Compound 37 was prepared by the method of Example 18 from Compound 2 .

Beispiel 38Example 38

Figure imgb0039
Figure imgb0039

1,3-Dichlor-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (38)1,3-dichloro-8-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 38 )

Verbindung 38 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 3 hergestellt.Compound 38 was prepared by the method of Example 18 from Compound 3 .

Beispiel 39Example 39

Figure imgb0040
Figure imgb0040

1,3-Dichfor-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (39)1,3-Dichfor-8-ethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 39 )

Verbindung 39 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 4 hergestellt.Compound 39 was prepared by the method of Example 18 from Compound 4 .

Beispiel 40Example 40

Figure imgb0041
Figure imgb0041

1,3-Dichlor-8-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kallumsalz (40)1,3-dichloro-8-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Callum Salt ( 40 )

Verbindung 40 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 5 hergestellt.Compound 40 was prepared by the method of Example 18 from Compound 5 .

Beispiel 41Example 41

Figure imgb0042
Figure imgb0042

1,3-Dichlor-8-fluor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (41)1,3-dichloro-8-fluoro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 41 )

Verbindung 41 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 6 hergestellt.Compound 41 was prepared by the method of Example 18 from Compound 6 .

Beispiel 42Example 42

Figure imgb0043
Figure imgb0043

1,3,8-Trichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (42)1,3,8-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 42 )

Verbindung 42 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 7 hergestellt.Compound 42 was prepared by the method of Example 18 from Compound 7 .

Beispiel 43Example 43

Figure imgb0044
Figure imgb0044

8-Brom-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (43)8-bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 43 )

Verbindung 43 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 8 hergestellt.Compound 43 was prepared by the method of Example 18 from compound 8 .

Beispiel 44Example 44

Figure imgb0045
Figure imgb0045

8-Iod-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (44)8-iodo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 44 )

Verbindung 44 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 9 hergestellt.Compound 44 was prepared by the method of Example 18 from compound 9 .

Beispiel 45Example 45

Figure imgb0046
Figure imgb0046

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6,8-dicarboxylat; Dikaliumsalz (45)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6,8-dicarboxylate; Dipotassium salt ( 45 )

Verbindung 45 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 10 hergestellt.Compound 45 was prepared by the method of Example 18 from Compound 10 .

Beispiel 46Example 46

Figure imgb0047
Figure imgb0047

1,3-Dichlor-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (46)1,3-dichloro-10-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 46 )

Verbindung 46 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 11 hergestellt.Compound 46 was prepared by the method of Example 18 from Compound 11 .

Beispiel 47Example 47

Figure imgb0048
Figure imgb0048

1,3-Dichlor-10-fluor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (47)1,3-dichloro-10-fluoro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 47 )

Verbindung 47 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 12 hergestellt.Compound 47 was prepared by the method of Example 18 from Compound 12 .

Beispiel 48Example 48

Figure imgb0049
Figure imgb0049

1,3,10-Trichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (48)1,3,10-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 48 )

Verbindung 31 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 13 hergestellt.Compound 31 was prepared by the method of Example 18 from Compound 13 .

Beispiel 49Example 49

Figure imgb0050
Figure imgb0050

10-Brom-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (49)10-bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 49 )

Verbindung 49 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 14 hergestellt.Compound 49 was prepared by the method of Example 18 from compound 14 .

Beispiel 50Example 50

Figure imgb0051
Figure imgb0051

10-Iod-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (50)10-iodo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 50 )

Verbindung 50 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 15 hergestellt.Compound 50 was prepared by the method of Example 18 from Compound 15 .

Beispiel 51Example 51

Figure imgb0052
Figure imgb0052

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6,10-dicarboxylat; Dikaliumsalz (51)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6,10-dicarboxylate; Dipotassium salt ( 51 )

Verbindung 51 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 16 hergestellt.Compound 51 was prepared by the method of Example 18 from Compound 16 .

Beispiel 529Example 529

Figure imgb0053
Figure imgb0053

1,3-Dichlor-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carboxylat; Kaliumsalz (52)1,3-dichloro-10-cyano-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluoren-6-carboxylate; Potassium salt ( 52 )

Verbindung 52 wurde nach dem Verfahren gemäß Beispiel 18 aus Verbindung 17 hergestellt.Compound 52 was prepared by the method of Example 18 from Compound 17 .

Beispiel 53: Allgemeine Darstellung der Salze mit Anionen am Beispiel des Hydrochloridsalzes der Verbindungen gemäß einem der Beispiele 1-17.Example 53: General presentation of the salts with anions using the example of the hydrochloride salt of the compounds according to one of Examples 1-17.

Ein Äquivalent der Verbindung gemäß einem der Beispiele 1 bis 17 wird in ca. 10 ml 2-Butanon je Gramm Substanz gelöst. Dann wird ein halbes Moläquivalent Wasser zugegeben, gefolgt von 1,1 Moläquivalenten Chlortrimethylsilan. Dann folgt Rühren über Nacht. Bildete sich auch bei Kühlung auf ca. 4 °C kein Hydrochlorid, wurde der Fällungsansatz im doppelten Volumen Wasser aufgenommen, mit drei kleinen Portionen Ether gewaschen, die wäßrige Phase mit wenig ca. 30 %iger Natronlauge alkalisch gestellt und dreimal mit Ether extrahiert ("Säure-Base-Extraktion"). Diese letzten Extrakte wurden wiederum vereinigt und einer erneuten Hydrochloridfällung zugeführt.One equivalent of the compound according to any one of Examples 1 to 17 is dissolved in about 10 ml of 2-butanone per gram of substance. Then half a molar equivalent of water is added, followed by 1.1 molar equivalents of chlorotrimethylsilane. Then stir overnight. Also formed with cooling hydrochloric acid at about 4 ° C, the precipitate was added in twice the volume of water, washed with three small portions of ether, the aqueous phase with little about 30% sodium hydroxide solution made alkaline and extracted three times with ether ("acid-base extraction "). These last extracts were combined again and fed to a fresh hydrochloride precipitation.

Die Verbindungen gemäß Beispiel 54 bis 70 sind nach dieser beispielhaften Vorschrift hergestellte Hydrochloridsalze der Verbindungen 1 bis 17.The compounds according to Examples 54 to 70 are hydrochloride salts of compounds 1 to 17 prepared by this exemplary procedure.

Beispiel 54Example 54

Figure imgb0054
Figure imgb0054

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (54)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 54 )

Verbindung 54 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 1 hergestellt.Compound 54 was prepared by the method of Example 53 from Compound 1 .

Beispiel 55Example 55

Figure imgb0055
Figure imgb0055

1,3-Dichlor-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (55)1,3-dichloro-10-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 55 )

Verbindung 55 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 2 hergestellt.Compound 55 was prepared by the method of Example 53 from Compound 2 .

Beispiel 56Example 56

Figure imgb0056
Figure imgb0056

1,3-Dichlor-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (56)1,3-dichloro-8-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 56 )

Verbindung 56 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 3 hergestellt.Compound 56 was prepared by the method of Example 53 from Compound 3 .

Beispiel 57Example 57

Figure imgb0057
Figure imgb0057

1,3-Dichlor-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (57)1,3-dichloro-8-ethyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 57 )

Verbindung 57 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 4 hergestellt.Compound 57 was prepared by the method of Example 53 from Compound 4 .

Beispiel 58Example 58

Figure imgb0058
Figure imgb0058

1,3-Dichlor-8-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (58)1,3-dichloro-8-methoxy-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 58 )

Verbindung 58 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 5 hergestellt.Compound 58 was prepared by the method of Example 53 from Compound 5 .

Beispiel 59Example 59

Figure imgb0059
Figure imgb0059

1,3-Dichlor-8-fluor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (59)1,3-dichloro-8-fluoro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 59 )

Verbindung 59 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 6 hergestellt.Compound 59 was prepared by the method of Example 53 from Compound 6 .

Beispiel 60Example 60

Figure imgb0060
Figure imgb0060

1,3,8-Trichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (60)1,3,8-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 60 )

Verbindung 60 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 7 hergestellt.Compound 60 was prepared by the method of Example 53 from Compound 7 .

Beispiel 61Example 61

Figure imgb0061
Figure imgb0061

8-Brom-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (61)8-bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 61 )

Verbindung 61 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 8 hergestellt.Compound 61 was prepared by the method of Example 53 from compound 8 .

Beispiel 62Example 62

Figure imgb0062
Figure imgb0062

8-Iod-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (62)8-iodo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 62 )

Verbindung 62 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 9 hergestellt.Compound 62 was prepared by the method of Example 53 from Compound 9 .

Beispiel 63Example 63

Figure imgb0063
Figure imgb0063

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6,8-dicarbonsäure; Hydrochloridsalz (63)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6,8-dicarboxylic acid; Hydrochloride salt ( 63 )

Verbindung 63 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 10 hergestellt.Compound 63 was prepared by the method of Example 53 from Compound 10 .

Beispiel 64Example 64

Figure imgb0064
Figure imgb0064

1,3-Dichlor-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (64)1,3-dichloro-10-methyl-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 64 )

Verbindung 64 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 11 hergestellt.Compound 64 was prepared by the method of Example 53 from Compound 11 .

Beispiel 65Example 65

Figure imgb0065
Figure imgb0065

1,3-Dichlor-10-fluor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (65)1,3-dichloro-10-fluoro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 65 )

Verbindung 65 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 12 hergestellt.Compound 65 was prepared by the method of Example 53 from Compound 12 .

Beispiel 66Example 66

Figure imgb0066
Figure imgb0066

1,3,10-Trichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (66)1,3,10-trichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 66 )

Verbindung 66 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 13 hergestellt.Compound 66 was prepared by the method of Example 53 from Compound 13 .

Beispiel 67Example 67

Figure imgb0067
Figure imgb0067

10-Brom-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (67)10-bromo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 67 )

Verbindung 67 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 14 hergestellt.Compound 67 was prepared by the method of Example 53 from Compound 14 .

Beispiel 68Example 68

Figure imgb0068
Figure imgb0068

10-Iod-1,3-dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (68)10-iodo-1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 68 )

Verbindung 68 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 15 hergestellt.Compound 68 was prepared by the method of Example 53 from Compound 15 .

Beispiel 69Example 69

Figure imgb0069
Figure imgb0069

1,3-Dichlor-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6,10-dicarbonsäure; Hydrochloridsalz (69)1,3-dichloro-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6,10-dicarboxylic acid; Hydrochloride salt ( 69 )

Verbindung 69 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 16 hergestellt.Compound 69 was prepared by the method of Example 53 from Compound 16 .

Beispiel 70Example 70

Figure imgb0070
Figure imgb0070

1,3-Dichlor-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluoren-6-carbonsäure; Hydrochloridsalz (70)1,3-dichloro-10-cyano-5,6,6a, 11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid; Hydrochloride salt ( 70 )

Verbindung 70 wurde nach dem Verfahren gemäß Beispiel 53 aus Verbindung 17 hergestellt.Compound 70 was prepared by the method of Example 53 from Compound 17 .

Beispiel 71Example 71 Rezeptorbindung (Glycin-Bindungsstelle des NMDA-Rezeptorkanals)Receptor binding (glycine binding site of the NMDA receptor channel)

Die Untersuchungen zur Bestimmung der Affinität der erfindungsgemäßen Verbindungen der Formel I zur Glycin-Bindungsstelle des NMDA-Rezeptorkanals wurde an Himmembran-Homogenaten (Homogenat von Cortex- und Hippocampus-Areal aus dem Him von männlichen Ratten, Stamm Wistar) durchgeführt [ B.M. Baron , B.W. Siegel, B.L. Harrison, R.S. Gross, C. Hawes and P.Towers, Journal of Pharmacology and Experimental Therapeutics, Vol. 279, S. 62.1996 ].
Hierzu wurde Cortex und Hippocampus aus frisch entnommenen Rattengehimen freipräpariert und in 5 mmol/l TRIS-Acetatpuffer, 0,32 mol/l Sacharose pH 7,4 (10 ml/g Frischgewicht) mit einem Potter-Homogenisator (Fa. Braun/Melsungen 10 Kolbenhübe bei 500 Upm) unter Eiskühlung homogenisiert und anschließend für 10 Minuten bei 1.000 g und 4°C zentrifugiert. Der erste Überstand wurde gesammelt und das Sediment erneut mit 5 mmol/l TRIS-Acetatpuffer, 0,32 mol/l Sacharose pH 7,4 (5 ml/g ursprüngliches Frischgewicht) mit dem Potter-Homogenisator (10 Kolbenhübe bei 500 Upm) unter Eiskühlung homogenisiert und für 10 Minuten bei 1.000 g und 4°C zentrifugiert. Der resultierende Überstand wurde mit dem Überstand aus der ersten Zentrifugation vereinigt und bei 17.000 g für 20 Minuten bei 4°C zentrifugiert. Der Überstand nach dieser Zentrifugation wurde verworfen und das Membran-sediment mit 5 mmol/l TRIS-Acetatpuffer pH 8,0 (20 ml/g ursprüngliches Frischgewicht) aufgenommen und mit 10 Kolbenhüben bei 500 Upm homogenisiert. Anschließend wurde das Membranhomogenat für 1 Stunde bei 4°C inkubiert für 30 Minuten bei 50.000 g und 4°C zentrifugiert. Der Überstand wurde verworfen und das Zentrifugen-röhrchen mit dem Membransediment mit Parafilm verschlossen und für 24 Stunden bei -20°C eingefroren. Am folgenden Tag wurde das Membransediment aufgetaut und mit eiskaltem 5 mmol/l TRIS-Acetatpuffer, 0,1 % Saponin (w/v) pH 7,0 (10 ml/g ursprüngliches Frischgewicht) aufgenommen und mit 10 Kolbenhüben bei 500 Upm homogenisiert und anschließend für 20 Minuten bei 50.000 g und 4°C zentrifugiert. Der resultierende Überstand wurde verworfen und das Sediment in einem kleinen Volumen mit 5 mmo/l TRIS-Acetatpuffer pH 7,0 (ca. 2 ml/g ursprüngliches Frischgewicht) aufgenommen und erneut mit 10 Kolbenhüben bei 500 Upm homogenisiert. Nach Bestimmung des Proteingehaltes wurde das Membranhomogenat mit 5 mmol/l TRIS-Acetatpuffer pH 7,0 auf eine Proteinkonzentration von 10 mg Protein/ml eingestellt und in Aliquoten bis zur Testung eingefroren.
Für den Rezeptorbindungstest wurden Aliquote aufgetaut 1:10 mit 5 mmo/l TRIS-Acetatpuffer pH 7,0 verdünnt, mit 10 Kolbenhüben bei 500 Upm mit dem Potter-Homogenisator (10 Kolbenhübe bei 500 Upm) unter Eiskühlung homogenisiert und für 60 Minuten bei 55.000 g bei 4°C zentrifugiert. Der Überstand wurde dekantiert und das Membransediment mit eiskaltem 50 mmol/l TRIS-Acetatpuffer pH 7,0 auf eine Proteinkonzentration von 1 mg/ml eingestellt und erneut mit 10 Kolbenhüben bei 500 Upm homogenisiert und unter Rühren auf einem Magnetrührer im Eisbad in Suspension gehalten. Von diesem Membranhomogenat wurden jeweils 100 µl je 1 ml-Ansatz im Rezeptorbindungstest eingesetzt (0,1 mg Protein/ml im Endansatz).
Im Bindungstest wurde als Puffer 50 mmol/l TRIS-Acetatpuffer pH 7,0 sowie als radioaktiver Ligand 1 nmol/l (3H)-MDL 105.519 (B.M. Baron et al. 1996) eingesetzt. Der Anteil an unspezifischer Bindung wurde in Anwesenheit von 1 mmol/l Glycin bestimmt.
In weiteren Ansätzen wurden die erfindungsgemäßen Verbindungen in Konzentrationsreihen zugegeben und die Verdrängung des radioaktiven Liganden aus seiner spezifischen Bindung an die Glycin-Bindungsstelle des NMDA-Rezeptorkanals ermittelt. Die jeweiligen Dreifachansätze wurden über 120 Minuten bei 4°C inkubiert und anschließend zur Bestimmung des an das Membranhomogenat gebundenen radioaktiven Liganden mittels Filtration durch Glasfaser-Filtermatten (GF/B) geerntet. Die auf den Glasfaser-Filtern zurückgehaltene Radioaktivität wurde nach Zugabe von Szintillator im β-Counter gemessen.
Die Affinität der erfindungsgemäßen Verbindungen zur Glycin-Bindungsstelle des NMDA-Rezeptorkanals wurde als IC50 (Konzentration mit 50 % Verdrängung des radioaktiven Liganden aus seiner spezifischen Bindung) nach dem Massenwirkungsgesetz mittels nichtlinearer Regression berechnet und ist in Tabelle 1 nach Umrechnung (nach der Cheng-Prussoff-Beziehung) als Ki-Wert (Mittelwert von 3 unabhängigen Versuchen) angegeben oder als prozentualer Anteil des zuvor gebundenen radioaktiven Liganden s.o., der bei einer Konzentration von 10 µmol/l der zu testenden erfindungsgemäßen Substanz aus seiner spezifischen Bindung verdrängt wird. Tabelle 1 Beispiel GlycinBindungsstelle des NMDA-Rezeptorkanals Ki (µmol/l) Verdrängung (%,10µmol/l) 1 0,053 100 The investigations for determining the affinity of the compounds of the formula I according to the invention for the glycine binding site of the NMDA receptor channel were carried out on Himmembran homogenates (homogenate of cortex and hippocampus area from the brain of male rats, strain Wistar) [ BM Baron, BW Siegel, BL Harrison, RS Gross, C. Hawes and P.Towers, Journal of Pharmacology and Experimental Therapeutics, Vol. 279, p. 62, 1996 ].
For this purpose, the cortex and hippocampus were prepared from freshly taken rat chickens and dissolved in 5 mmol / l TRIS acetate buffer, 0.32 mol / l sucrose pH 7.4 (10 ml / g fresh weight) with a Potter homogenizer (Braun / Melsungen 10 Piston strokes at 500 rpm) with ice cooling homogenized and then centrifuged for 10 minutes at 1000 g and 4 ° C. The first supernatant was collected and the sediment was resuspended with 5 mmol / l TRIS acetate buffer, 0.32 mol / l sucrose pH 7.4 (5 ml / g original fresh weight) with the Potter homogenizer (10 strokes at 500 rpm) Ice cooling homogenized and centrifuged for 10 minutes at 1000 g and 4 ° C. The resulting supernatant was combined with the supernatant from the first centrifugation and centrifuged at 17,000 g for 20 minutes at 4 ° C. The supernatant after this centrifugation was discarded and the membrane sediment was taken up with 5 mmol / l TRIS acetate buffer pH 8.0 (20 ml / g original fresh weight) and homogenized with 10 strokes of the flask at 500 rpm. Subsequently, the membrane homogenate was incubated for 1 hour at 4 ° C for 30 minutes at 50,000 g and centrifuged at 4 ° C. The supernatant was discarded and the centrifuge tube sealed with the membrane sediment with parafilm and frozen at -20 ° C for 24 hours. The following day, the membrane sediment was thawed and taken up with ice cold 5 mmol / l TRIS acetate buffer, 0.1% saponin (w / v) pH 7.0 (10 ml / g original fresh weight) and homogenized with 10 strokes at 500 rpm then centrifuged for 20 minutes at 50,000 g and 4 ° C. The resulting supernatant was discarded and the sediment was taken up in a small volume with 5 mMo / l TRIS acetate buffer pH 7.0 (about 2 ml / g original fresh weight) and homogenized again with 10 strokes of the flask at 500 rpm. After determining the protein content, the membrane homogenate was adjusted to a protein concentration of 10 mg protein / ml with 5 mmol / l TRIS acetate buffer pH 7.0 and frozen in aliquots until testing.
For the receptor binding assay, aliquots were thinned 1:10 with 5 mM Tris acetate buffer pH 7.0, homogenized with 10 strokes at 500 rpm using the Potter homogenizer (10 strokes at 500 rpm) with ice cooling and for 60 minutes at 55,000 g centrifuged at 4 ° C. The supernatant was decanted and the membrane sediment with ice-cold 50 mmol / l TRIS acetate buffer pH 7.0 to a protein concentration of 1 mg / ml adjusted and again homogenized with 10 strokes of the piston at 500 rpm and kept in suspension with stirring on a magnetic stirrer in an ice bath. From this membrane homogenate in each case 100 .mu.l were used per 1 ml batch in the receptor binding test (0.1 mg protein / ml in the final batch).
In the binding test, the buffer used was 50 mmol / l TRIS acetate buffer pH 7.0 and the radioactive ligand 1 nmol / l ( 3 H) MDL 105,519 (Baron BM et al., 1996). The proportion of non-specific binding was determined in the presence of 1 mmol / l glycine.
In further mixtures, the compounds according to the invention were added in concentration series and the displacement of the radioactive ligand from its specific binding to the glycine binding site of the NMDA receptor channel was determined. The respective triplicate batches were incubated for 120 minutes at 4 ° C. and then harvested by filtration through glass fiber filter mats (GF / B) to determine the radioactive ligand bound to the membrane homogenate. The radioactivity retained on the glass fiber filters was measured after addition of scintillator in the β-counter.
The affinity of the compounds according to the invention for the glycine binding site of the NMDA receptor channel was calculated as IC 50 (concentration with 50% displacement of the radioactive ligand from its specific binding) according to the law of mass action by means of nonlinear regression and is shown in Table 1 after conversion (according to the Cheng Prussoff relationship) as the Ki value (mean of 3 independent experiments) or as a percentage of the previously bound radioactive ligand so that is displaced from its specific binding at a concentration of 10 .mu.mol / l of the substance to be tested inventive substance. Table <b> 1 </ b> example Glycine binding site of the NMDA receptor channel Ki (μmol / l) Displacement (%, 10μmol / l) 1 0.053 100

Beispiel 72Example 72 Formalin-Test, RatteFormalin test, rat

Die Untersuchungen zur Bestimmung der antinociceptiven Wirkung der erfindungsgemäßen Verbindungen der Formel I wurden im Formalin-Test an männlichen Ratten (Sprague-Dawley, 150 -170 g) durchgeführt. Im Formalin-Test werden die erste (frühe) Phase (0-15 min nach Formalin-Injektion) und die zweite (späte) Phase (15 - 60 min nach Formalin-Injektion) unterschieden ( D. Dubuisson, S.G. Dennis, Pain 4, 161 -174 (1977 )). Die frühe Phase stellt als direkte Reaktion auf die Formalin-Injektion ein Modell für Akutschmerz dar, während die späte Phase als Modell für persistierenden (chronischen) Schmerz angesehen wird ( T.J. Coderre, J. Katz, A.L. Vaccarino, R. Melzack, Pain, Vol. 52, S. 259, 1993 ). Die erfindungsgemäßen Verbindungen wurden in der zweiten Phase des Formalin-Tests untersucht, um Aussagen über Substanzwirkungen im chronisch/entzündlichen Schmerz zu erhalten. Durch eine einmalige subkutane Formalin-Injektion (50 µl, 5 %ig) in die dorsale Seite der rechten Hinterpfote wurde bei freibeweglichen Versuchstieren eine nociceptive Reaktion induziert, die sich in folgenden Verhaltensparametern darstellt: Heben und Halten der betroffenen Pfote (Score 1), Schütteln bzw. Zucken (Score 2), Lecken und Beißen (Score 3). Die aufgrund der Formalininjektion ausgelösten differierenden Verhaltensweisen wurden durch Beobachtung der Tiere in der späten Phase des Formalin-Tests kontinuierlich erfaßt und in einer Bewertung unterschiedlich gewichtet. Normalverhalten, bei dem das Tier alle vier Pfoten gleichmäßig belastet, wurde als Score 0 registriert. Abhängig von der Applikationsart der erfindungsgemäßen Verbindungen wurde der Applikationszeitpunkt vor der Formalin-Injektion gewählt (intraperitoneal: 15 min, intravenös: 5 min). Nach Injektion von Substanzen, die im Formalin-Test antinozizeptiv wirksam sind, sind die beschriebenen Verhaltensweisen (Score 1 - 3) der Tiere reduziert, evtl. sogar aufgehoben. Der Vergleich erfolgte mit Kontrolltieren, die Vehikel (Lösungsmittel) vor Formalinapplikation erhalten hatten. Das nozizeptive Verhalten wurde als sogenannte Schmerz-Rate (Pain-Rate, PR) berechnet. Die verschiedenen Verhaltensparameter erhielten eine unterschiedliche Gewichtung (Faktor 0, 1, 2, 3). Die Kalkulation erfolgte in Teilintervallen von 3 min nach folgender Formel: PR = T 0 × 0 + ( T 1 × 1 ) + ( T 2 × 2 ) + ( T 3 × 3 ) / 180 ,

Figure imgb0071

wobei T0, T1, T2, und T3 jeweils der Zeit in Sekunden entspricht, in der das Tier die Verhaltensweisen 0, 1, 2 oder 3 zeigte. Substanz- und Vehikelgruppen umfassen jeweils n = 10 Tiere. Basierend auf den PR-Berechnungen wurde die Substanzwirkung als Änderung gegen Kontrolle in Prozent ermittelt. Die ED50-Berechnungen erfolgten mittels Regressionsanalyse.
Alle untersuchten erfindungsgemäßen Verbindungen zeigten eine mittelstarke bis starke Hemmung der durch Formalin induzierten Nociception.
Die Ergebnisse ausgewählter Untersuchungen im Formalin-Test Ratte sind in der nachfolgenden Tabelle zusammengefaßt. Tabelle 2: Verbindung Applikationsart ED50 1 i.v. 7,27 mg/kg The investigations for the determination of the antinociceptive activity of the compounds of the formula I according to the invention were carried out in a formalin test on male rats (Sprague-Dawley, 150-170 g). In the formalin test, the first (early) phase (0-15 min after formalin injection) and the second (late) phase (15-60 min after formalin injection) are distinguished ( D. Dubuisson, SG Dennis, Pain 4, 161-174 (1977 )). The early phase represents a model of acute pain as a direct response to formalin injection, while the late phase is considered a model of persistent (chronic) pain ( TJ Coderre, J. Katz, AL Vaccarino, R. Melzack, Pain, Vol. 52, p. 259, 1993 ). The compounds according to the invention were investigated in the second phase of the formalin test in order to obtain statements about substance effects in chronic / inflammatory pain. A single subcutaneous injection of formalin (50 μl, 5%) into the dorsal side of the right hindpaw induced a nociceptive reaction in freely moving test animals, which is reflected in the following behavioral parameters: lifting and holding the affected paw (score 1), shaking or twitching (score 2), licking and biting (score 3). The differing behaviors due to formalin injection were continuously monitored by observation of the animals in the late phase of the formalin test and weighted differently in a score. Normal behavior, in which the animal evenly loaded all four paws, was registered as score 0. Depending on the mode of administration of the compounds according to the invention, the application time before the formalin injection was selected (intraperitoneal: 15 min, intravenous: 5 min). After injection of substances which are antinociceptive in the formalin test, the described behavior (score 1 - 3) of the animals are reduced, possibly even reversed. The comparison was done with control animals that had received vehicle (solvent) before formalin application. The nociceptive behavior was calculated as the so-called pain rate (PR). The different behavioral parameters received a different weighting (factor 0, 1, 2, 3). The calculation was carried out in subintervals of 3 min according to the following formula: PR = T 0 × 0 + ( T 1 × 1 ) + ( T 2 × 2 ) + ( T 3 × 3 ) / 180 .
Figure imgb0071
where T 0 , T 1 , T 2 , and T 3 each correspond to the time in seconds in which the animal showed the behaviors 0, 1, 2 or 3. Substance and vehicle groups each comprise n = 10 animals. Based on the PR calculations, the substance effect was determined as a change from control in percent. The ED 50 calculations were performed by regression analysis.
All investigated compounds of the invention showed a moderate to strong inhibition of formalin-induced nociception.
The results of selected studies in the rat formalin test are summarized in the following table. <u> Table 2: </ u> connection administration ED 50 1 iv 7.27 mg / kg

Beispiel 73: Parenterale Applikationsform.Example 73: Parenteral administration form.

38,5 g der Verbindung 1 werden in 1 l Wasser für Injektionszwecke bei Raumtemperatur gelöst und anschließend durch Zugabe von wasserfreier Glukose für Injektionszwecke auf isotone Bedingungen eingestellt.38.5 g of compound 1 are dissolved in 1 liter of water for injection at room temperature and then adjusted to isotonic conditions by adding anhydrous glucose for injection.

Claims (11)

  1. Substituted 5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]-fluorene-6-carboxylic acid derivatives of general formula I:
    Figure imgb0074
     in the illustrated form, in the form of their acids or bases, in the form of their salts, in the form of their solvates, in the form of their racemates or their pure stereoisomers, or in the form of mixtures of the stereoisomers, in any desired mixing ratio,
    in which formula
    R1, R2, R3 and R4 independently of one another are selected from H, F, Cl, Br, I, CN, NH2, CH3, C2H5, n-propyl, i-propyl, i-butyl, sec-butyl, n-butyl, t-butyl, CF3, CHF2, SH, OH, OCH3, OC2H5, C(O)OH, C(O)OCH3 and C(O)OC2H5,
    R5 = H,
    R6 = H,
    R7= H,
    R8= Cl,
    R9= H and
    R10 = Cl.
  2. Substituted 5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]-fluorene-6-carboxylic acid derivatives according to Claim 1, characterized in that they are pure enantiomers or diastereoisomers, or in that the enantiomers or diastereoisomers are in any desired mixing ratio.
  3. Substituted 5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]-fluorene-6-carboxylic acid derivatives according to Claim 1 or 2, characterized in that they are the following compounds or their salts:
    - 1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo-[c]fluorene-6-carboxylic acid,
    - 1,3-dichloro-10-methoxy-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid,
    - 1,3-dichloro-8-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid,
    - 1,3-dichloro-8-ethyl-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid,
    - 1,3-dichloro-8-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid,
    - 1,3,8-trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo [c] fluorene-6-carboxylic acid,
    - 8-bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid,
    - 8-iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid,
    - 1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo-[c]fluorene-6,8-dicarboxylic acid,
    - 1,3-dichloro-10-methyl-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid,
    - 1,3-dichloro-10-fluoro-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid,
    - 1,3,10-trichloro-5,6,6a,11b-tetrahydro-7-oxa-5-aza-benzo[c]fluorene-6-carboxylic acid,
    - 10-bromo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid,
    - 10-iodo-1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid,
    - 1,3-dichloro-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo-[c]fluorene-6,10-dicarboxylic acid or
    - 1,3-dichloro-10-cyano-5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid.
  4. Substituted 5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]-fluorene-6-carboxylic acid derivatives according to one of Claims 1 to 3, characterized in that they are in the form of their alkali metal salts, preferably the potassium of sodium salts, or in the form of the salts of inorganic acids, preferably the hydrochloride.
  5. Process for the preparation of substituted 5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid derivatives according to Claim 1, characterized in that 3,5-dichloroaniline of formula II:
    Figure imgb0075
     is reacted with glyoxylic acid of formula III and a benzofuran IV, in which R1, R2, R3 and R4 independently of one another are each as defined in Claim 1, in the presence of trifluoroacetic acid at between 0°C and 100°C.
  6. Process according to Claim 5, characterized in that the reaction time is 0.25 - 12 hours, preferably at most 2 h, and the reaction takes place preferably at a temperature between 20 and 40°C, particularly preferably at room temperature, and/or is a one-pot reaction.
  7. Drug containing, as active substance, at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]-fluorene-6-carboxylic acid derivative according to one of Claims 1 to 3, and optionally containing suitable additives and/or auxiliary substances and/or optionally other active substances.
  8. Use of at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid derivative according to one of Claims 1 to 3 for the preparation of a drug for the treatment of pain and/or for the treatment of migraine.
  9. Use of at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid derivative according to Claim 8 for the preparation of a drug for the treatment of neuropathic and/or chronic pain.
  10. Use of at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid derivative according to one of Claims 1 to 3 for the preparation of a drug for the treatment of urinary incontinence, itching, tinnitus aurium and/or diarrhoea.
  11. Use of at least one substituted 5,6,6a,11b-tetrahydro-7-oxa-5-azabenzo[c]fluorene-6-carboxylic acid derivative according to one of Claims 1 to 3 for the preparation of a drug for the treatment/prophylaxis of epilepsy, Parkinson's disease, Huntington's disease, glaucoma, osteoporosis, ototoxicity, withdrawal symptoms associated with alcohol and/or drug abuse, stroke, cerebral ischaemia, cerebral infarction, cerebral oedema, hypoxia and anoxia, and/or for anxiolysis and/or anaesthesia.
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